ITMI941868A1 - DERIVATIVES OF 2-AMINO-1, 2, 3, 4-TETRAIDRONAFTALENE ACTIVE IN THE CARDIOVASCULAR SYSTEM - Google Patents
DERIVATIVES OF 2-AMINO-1, 2, 3, 4-TETRAIDRONAFTALENE ACTIVE IN THE CARDIOVASCULAR SYSTEM Download PDFInfo
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- ITMI941868A1 ITMI941868A1 IT001868A ITMI941868A ITMI941868A1 IT MI941868 A1 ITMI941868 A1 IT MI941868A1 IT 001868 A IT001868 A IT 001868A IT MI941868 A ITMI941868 A IT MI941868A IT MI941868 A1 ITMI941868 A1 IT MI941868A1
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- Prior art keywords
- hydrogen
- alkyl
- solution
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- 210000000748 cardiovascular system Anatomy 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- -1 NHS02NH2 Chemical group 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 2
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- HVZWVEKIQMJYIK-UHFFFAOYSA-N nitryl chloride Chemical compound [O-][N+](Cl)=O HVZWVEKIQMJYIK-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 4
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 1
- 101100097467 Arabidopsis thaliana SYD gene Proteins 0.000 claims 1
- 229910003204 NH2 Inorganic materials 0.000 claims 1
- 229910006069 SO3H Inorganic materials 0.000 claims 1
- 101100495925 Schizosaccharomyces pombe (strain 972 / ATCC 24843) chr3 gene Proteins 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 abstract description 4
- 208000001647 Renal Insufficiency Diseases 0.000 abstract description 3
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 3
- 201000006370 kidney failure Diseases 0.000 abstract description 3
- 208000037849 arterial hypertension Diseases 0.000 abstract description 2
- 200000000007 Arterial disease Diseases 0.000 abstract 1
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract 1
- 230000000302 ischemic effect Effects 0.000 abstract 1
- 230000002093 peripheral effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 239000000243 solution Substances 0.000 description 77
- 239000002904 solvent Substances 0.000 description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- 239000000543 intermediate Substances 0.000 description 46
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
- 238000003756 stirring Methods 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 30
- 238000001704 evaporation Methods 0.000 description 29
- 230000008020 evaporation Effects 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 229940035423 ethyl ether Drugs 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- 239000002253 acid Substances 0.000 description 19
- 238000004587 chromatography analysis Methods 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- 239000012071 phase Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 229960003638 dopamine Drugs 0.000 description 15
- 239000003480 eluent Substances 0.000 description 15
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 9
- RYBJORHCUPVNMB-UHFFFAOYSA-N dopexamine Chemical group C1=C(O)C(O)=CC=C1CCNCCCCCCNCCC1=CC=CC=C1 RYBJORHCUPVNMB-UHFFFAOYSA-N 0.000 description 9
- 150000002431 hydrogen Chemical class 0.000 description 9
- 230000003291 dopaminomimetic effect Effects 0.000 description 8
- 229960001857 dopexamine Drugs 0.000 description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
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- 239000000725 suspension Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- LCGFVWKNXLRFIF-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-2-amine Chemical class C1=CC=C2CC(N)CCC2=C1 LCGFVWKNXLRFIF-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
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- 239000007983 Tris buffer Substances 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
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- 238000007796 conventional method Methods 0.000 description 3
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- WDJGPVYIVAPBFF-YDALLXLXSA-N (2s)-5,6-dimethoxy-n-propyl-1,2,3,4-tetrahydronaphthalen-2-amine;hydrobromide Chemical compound Br.C1=CC(OC)=C(OC)C2=C1C[C@@H](NCCC)CC2 WDJGPVYIVAPBFF-YDALLXLXSA-N 0.000 description 2
- FRKJDYFPVFMCAK-PPHPATTJSA-N (6s)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1,2-diol;hydrobromide Chemical compound Br.OC1=CC=C2C[C@@H](NCCC)CCC2=C1O FRKJDYFPVFMCAK-PPHPATTJSA-N 0.000 description 2
- MGBKJKDRMRAZKC-UHFFFAOYSA-N 3-aminobenzene-1,2-diol Chemical group NC1=CC=CC(O)=C1O MGBKJKDRMRAZKC-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- KOQCISGPATVUJH-UHFFFAOYSA-N 6-(1,3-dioxoisoindol-2-yl)hexanoyl chloride Chemical compound C1=CC=C2C(=O)N(CCCCCC(=O)Cl)C(=O)C2=C1 KOQCISGPATVUJH-UHFFFAOYSA-N 0.000 description 2
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- GOTMKOSCLKVOGG-UHFFFAOYSA-N SCH 23390 Chemical compound C1N(C)CCC2=CC(Cl)=C(O)C=C2C1C1=CC=CC=C1 GOTMKOSCLKVOGG-UHFFFAOYSA-N 0.000 description 2
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- 125000002252 acyl group Chemical group 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
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- 229910052740 iodine Inorganic materials 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- FDJMUIFLWLYSNU-UHFFFAOYSA-N n-phenylmethoxy-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1CC2=CC=CC=C2CC1NOCC1=CC=CC=C1 FDJMUIFLWLYSNU-UHFFFAOYSA-N 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 2
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
- C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
- C07C215/80—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring containing at least two amino groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
Description
"Derivati del 2-ammino-1 ,2,3,4-tetraidronaftalene- attivi sul sistema cardiovascolare" "Derivatives of 2-amino-1, 2,3,4-tetrahydronaphthalene - active on the cardiovascular system"
Descrizione Description
La presente invenzione riguarda composti attivi sul cardiovascolare ed in particolare riguarda derivati del 2-ammino-1,2,3,4-tetraidro-naftalene ed il loro uso in campo terapeutico. The present invention relates to cardiovascular active compounds and in particular relates to derivatives of 2-amino-1,2,3,4-tetrahydro-naphthalene and their use in the therapeutic field.
E' noto che diversi 2-ammino-1,2,3,4-tetraidro-naftaleni ossij drilati sono agonisti dei recettori dopaminergici e sono statil condotti molti studi di relazione attività-struttura per indii viduare le caratteristiche strutturali in grado di assicurare la migliore attività dopaminergica ed evitare, nello stesso tempo, gli effetti indesiderati della dopamina. It is known that various 2-amino-1,2,3,4-tetrahydro-naphthalenes oxydrylate are dopaminergic receptor agonists and many activity-structure relationship studies have been conducted to identify the structural characteristics capable of ensuring the best possible dopaminergic activity and avoid, at the same time, the undesirable effects of dopamine.
Un'interessante raccolta di questi studi è contenuta nel lavoro pubblicato da H.E. Katerinopoulos e D.I. Schuster in Drugs of the Future,voi. 12(3),pagg.223-253, (1987). An interesting collection of these studies is contained in the work published by H.E. Katerinopoulos and D.I. Schuster in Drugs of the Future, Vol. 12 (3), pp. 223-253, (1987).
Tuttavia,nonostante i numerosi studi la topologia dei recettori dopaminergici non è stata ancora chiarita ed una serie di modelli recettoriali è stata proposta nell'ultimo decennio. Nel campo dei composti strutturalmente correiabili alla dopamina e/o al 2-ammino-1,2,3,4-tetraidro-naftalene,alcuni autori hanno individuato nella presenza di un gruppo alchilico c-c sulla funzione amminica uno dei requisiti per l’attività dopaminergica mentre i requisiti strutturali del secondo sostituente sull'animino gruppo non sono stati ancora identificati. However, despite numerous studies, the topology of dopaminergic receptors has not yet been elucidated and a series of receptor models have been proposed in the last decade. In the field of compounds structurally correctable to dopamine and / or 2-amino-1,2,3,4-tetrahydro-naphthalene, some authors have identified the presence of a c-c alkyl group on the amino function as one of the requisites for dopaminergic activity while the structural requirements of the second substituent on the animino group have not yet been identified.
Ci sono però numerosi esempi in letteratura che mostrano come, in realtà, le caratteristiche strutturali dei due sostituent sull’amminogruppo possano essere estremamente,varie e come piccole variazioni della molecola possano influenzare notevolmente l'attività farmacologica sia in termini quantitativi sia in termini qualitativi. However, there are numerous examples in the literature that show how, in reality, the structural characteristics of the two substituents on the amino group can be extremely varied and how small variations of the molecule can greatly influence the pharmacological activity both in quantitative and qualitative terms.
Tra gli esempi più significativi citiamo i seguenti. Among the most significant examples we mention the following.
La domanda di brevetto europeo n° 72061 (Fisons PLC) descrive, tra gli altri, dopamine ed amminotetraidronaftaleni aventi una porzione amminica mono- o di-sostituita di formula European patent application n ° 72061 (Fisons PLC) describes, among others, dopamine and aminotetrahydronaphthalenes having a mono- or di-substituted amino portion of formula
in cui in which
X è una catena -(CH2)n-, eventualmente sostituita da ossidrili; nè un numero intero compreso tra 1 e 7; R1 ed R2,uguali o diversi tra loro, sono idrogeno, alchile o fenile; D2 è un idrogeno, alchile, fenile; alchile sostituito da imo o più ossidrili,piridili, fenili; alchile sostituito da fenile a sua volta sostituito da alogeno, alchile, ammino, alcossi o nitro; oppure Da può essere un residuo feniletilenico o tetraidro naftalenico eventualmente mono- o di-idrossi sostituito. X is an - (CH2) n- chain, optionally substituted by hydroxyls; nor an integer between 1 and 7; R1 and R2, the same or different from each other, are hydrogen, alkyl or phenyl; D2 is a hydrogen, alkyl, phenyl; alkyl substituted by imo or more hydroxyls, pyridyls, phenyls; alkyl substituted by phenyl in turn substituted by halogen, alkyl, amino, alkoxy or nitro; or Da can be a phenylethylene or tetrahydro naphthalene residue, optionally mono- or di-hydroxy substituted.
Tra i composti descritti nella domanda di brevetto europeo 72061, il composto di formula Among the compounds described in the European patent application 72061, the compound of formula
le cui denominazione comune internazionale è dopexamina (The Merck Index - XI ed.,n° 3418,pag. 538) è l’unico composto] per quanto di nostra conoscenza, che è stato sviluppato ed è utilizzato in terapia nel trattamento acuto dello scompenso. E' significativo che la dopexamina, pur essendo stata scelta! tra i numerosi composti descritti ed esemplificati nella domanda di brevetto europeo n° 72061, sia un agonista dei recettori dopaminergici meno attivo della dopamina e, come la dopamina stessa, non assorbito quando somministrato per via orale [A. Fitton e P.Benfield,Drugs,32.(2), 308-330, (1990)]. whose common international name is dopexamine (The Merck Index - XI ed., n ° 3418, p. 538) is the only compound] to the best of our knowledge, which has been developed and is used in therapy in the acute treatment of heart failure . It is significant that dopexamine, despite having been chosen! among the numerous compounds described and exemplified in European patent application n ° 72061, is a dopamine receptor agonist less active than dopamine and, like dopamine itself, not absorbed when administered orally [A. Fitton and P. Benfield, Drugs, 32. (2), 308-330, (1990)].
La domanda di brevetto europeo n° 142283 (Fisons PLC) descrive una classe di composti analoghi della dopexamina in cui l'amminogruppo della porzione dopaminica rimane secondarlo. European patent application No. 142283 (Fisons PLC) describes a class of dopexamine analogous compounds in which the amino group of the dopamine portion remains secondary.
Sono apparsi in letteratura diversi composti a struttura catecolamminica aventi lo scopo di mantenere le proprietà favorevoli della dopexamina anche quando somministrati per via orale oppure di accrescere la selettività verso i recettori dopaminergici. Various compounds with a catecholamine structure have appeared in the literature with the aim of maintaining the favorable properties of dopexamine even when administered orally or of increasing the selectivity towards dopaminergic receptors.
Tra questi particolarmente interessanti sono quelli descritti nella domanda di brevetto europeo .n° 321968 aventi la-seguente Among these, particularly interesting are those described in European patent application No. 321968 having the following
R ed R1,uguali o diversi tra loro. sono idrogeno o acile derivante da un acido carbossilico alifatico, aromatico o eteroaromatico, da un acido carbonico o carbammico o da un acido fosfo-j rico; n e p sono numeri interi scelti tra 0 e 1;m è un numero intero scelto tra 1, 2, 3 e A così che n+p=1 ed m+n è 2, 3 o 4; R2 ed R3,uguali o diversi tra loro, sono idrogeno, alogeno, alchile o alcossi. R and R1, the same or different from each other. they are hydrogen or acyl derived from an aliphatic, aromatic or heteroaromatic carboxylic acid, from a carbonic or carbamic acid or from a phosphoric acid; n and p are integers chosen from 0 to 1; m is an integer chosen from 1, 2, 3 and A so that n + p = 1 and m + n is 2, 3 or 4; R2 and R3, the same or different from each other, are hydrogen, halogen, alkyl or alkoxy.
Questi composti sono agonisti dei recettori dopaminergici D1 j D2, presentano contemporaneamente un effetto ai-antagoniste, non interagiscono con gli altri sistemi recettoriali,ma per essere attivi per somministrazione orale devono essere trasformati in adatti pro-drugs. These compounds are agonists of dopaminergic D1 j D2 receptors, simultaneously have an ai-antagonist effect, do not interact with other receptor systems, but to be active for oral administration they must be transformed into suitable pro-drugs.
Ancor più interessanti sono i composti descritti nella domanda di brevetto intemazionale UO 93/19036 Even more interesting are the compounds described in the international patent application UO 93/19036
che sono agonisti dopaminergici più potenti della dopamina e non selettivi verso un particolare sottotipo recettoriale, che non interagiscono con altri sistemi recettoriali e che, nel contempo, non presentano rispetto alla dopamina né gli effetti collaterali né gli aspetti terapeuticamente svantaggiosi. which are dopaminergic agonists more powerful than dopamine and non-selective towards a particular receptor subtype, which do not interact with other receptor systems and which, at the same time, do not present with respect to dopamine either side effects or therapeutically disadvantageous aspects.
I composti descritti nella suddetta domanda di brevetto intemazionale hanno la seguente formula generale: The compounds described in the aforementioned international patent application have the following general formula:
in cui in which
R1 ed R2,uguali o diversi tra loro, sono atomi di idrogeno o gruppi ΟΥ';Y ed Y’,uguali o diversi tra loro, sono atomi di idrogeno o gruppi acile derivanti da un acido carbossilico' alifatico, aromatico o eteroaromatico,da un acido carbonico oj carbammico o da un acido fosforico; 1 o 2;n.è un numero) intero tra 3 e 7;R3-è idrogeno o alchile C1,-4; R4 ed R5, uguali o diversi tra loro, sono idrogeno, alogeno, alchile o alcossi C1-C3. R1 and R2, the same or different from each other, are hydrogen atoms or ΟΥ 'groups; Y and Y', equal or different from each other, are hydrogen atoms or acyl groups deriving from an aliphatic, aromatic or heteroaromatic carboxylic acid, from a carbonic or carbamic acid or a phosphoric acid; 1 or 2; n. Is an integer) between 3 and 7; R3-is hydrogen or C1, -4 alkyl; R4 and R5, the same or different from each other, are hydrogen, halogen, alkyl or C1-C3 alkoxy.
Abbiamo ora trovato degli agonisti dei recettori- dopaminergici più potenti della dopamina e degli altri composti noti sopra descritti, che sono sostanzialmente privi di interazione con gli altri sistemi recettoriali e che sono assorbibili per via orale con lunga durata d'azione. We have now found dopamine receptor agonists more potent than dopamine and the other known compounds described above, which are substantially free of interaction with other receptor systems and which are orally absorbable with long duration of action.
Costituiscono pertanto oggetto della presente invenzione i composti di formula Therefore, the compounds of formula form an object of the present invention
in cui in which
m è un numero intero scelto tra 4, 5, 6, 7 ed 8; m is an integer chosen from 4, 5, 6, 7 and 8;
R, RT ed R" sono atomi di idrogeno o gruppi OH,purché almeno uno tra R, R’ ed R" sia un atomo di idrogeno ma R,R' ed RT non siano tutti contemporaneamente atomi di idrogeno ed R' è R" non siano ambedue contemporaneamente gruppi OH; J oppure uno tra R’ ed R" è un gruppo ', CH2OH o CH3 e l'altro è idrogeno; R, RT and R "are hydrogen atoms or OH groups, provided that at least one of R, R 'and R" is a hydrogen atom but R, R' and RT are not all hydrogen atoms at the same time and R 'is R " are not both OH groups at the same time; J or one of R 'and R "is a group', CH2OH or CH3 and the other is hydrogen;
R1 ed R2,uguali o diversi tra loro, sono atomi di idrogeno^ gruppi alchile C1-C3 o, insieme all'atomo di carbonio cui sono legati, formano un ciclopropile; R1 and R2, the same or different from each other, are hydrogen atoms, C1-C3 alkyl groups or, together with the carbon atom to which they are bonded, form a cyclopropyl;
n è un numero intero scelto tra 0, 1, 2, 3 e 4; n is an integer chosen from 0, 1, 2, 3 and 4;
p è un numero intero scelto tra 0 e 1; p is an integer chosen between 0 and 1;
R3 è un atomo di idrogeno o un gruppo alchile C,-C.*; ;;;;oppure un legame semplice; ;R4, Re ed R*,uguali o diversi tra loro, sono idrogeno, OH, alogeno, C1-C4 alchile, C1,-C4» alcossi,nitro, C1,-C4 elchiltio, NHa,mono- o di-C1-C4 alchilaminino, SH, C1-C4 alchilI-solfonil, NHCHO, C-1-C4 alchilcarbonilamroino,NHCONHa, C1-C4 alchilsolfonilammino, C1-C4 alchilamminosolfonil, SO2NH2, o fenile;oppure R3 is a hydrogen atom or a C, -C. * Alkyl group; ;;;; or a simple link; ; R4, Re and R *, the same or different from each other, are hydrogen, OH, halogen, C1-C4 alkyl, C1, -C4 »alkoxy, nitro, C1, -C4 elkylthio, NHa, mono- or di-C1- C4 alkylamine, SH, C1-C4 alkylI-sulfonyl, NHCHO, C-1-C4 alkylcarbonylamroine, NHCONHa, C1-C4 alkylsulfonylamino, C1-C4 alkylaminosulfonyl, SO2NH2, or phenyl; or
R4 ed R5, in posizione orto fra loro, insieme formano una catena costituita da 3 o 4 gruppi scelti tra 0 ed NH; R4 and R5, in ortho position to each other, together form a chain consisting of 3 or 4 groups selected between 0 and NH;
R7 è un atomo di idrogeno o un gruppo alchile C1-C4; R7 is a hydrogen atom or a C1-C4 alkyl group;
R8 è un atomo di idrogeno; R8 is a hydrogen atom;
oppure or
R7 ed R8 insieme formano una catena -CH2- o -CH2-CH2-; o R4,quando in posizione orto rispetto ad X, può formare con R7 una catena -CH2- o -CH2-CH2-; o R7 and R8 together form a -CH2- or -CH2-CH2- chain; or R4, when in ortho position with respect to X, can form with R7 a -CH2- or -CH2-CH2- chain; or
quando x=o when x = o
R4, quando in posizione orto rispetto ad X, può formare con R3 una catena -CH2-0-; R4, when in ortho position with respect to X, can form a chain -CH2-0- with R3;
l'asterisco indica un atomo di carbonio asimmetrico; the asterisk indicates an asymmetric carbon atom;
purché so long as
a) quando P.=1. X sia un gruppo N(R2); a) when P. = 1. X is a group N (R2);
b) quando Y è N(R7), R7 è idrogeno o alchile ed R3 è idrogeno, almeno uno tra R4 R5 ed R6 sia diverso da idrogeno, alogeno, C-1-C.4 alchile e C1-C4 alcossi; b) when Y is N (R7), R7 is hydrogen or alkyl and R3 is hydrogen, at least one of R4 R5 and R6 is different from hydrogen, halogen, C-1-C.4 alkyl and C1-C4 alkoxy;
c) quando Y è N(R7), R7 è idrogeno o‘alchile,R3 è idrogeno ed X è un legame semplice, almeno uno tra R4,R5 ed R6 sia diverso da idrogeno, alogeno, NHa, C1,-C4 alchile, C1,-C4 alcossi e nitro; c) when Y is N (R7), R7 is hydrogen or alkyl, R3 is hydrogen and X is a simple bond, at least one between R4, R5 and R6 is different from hydrogen, halogen, NHa, C1, -C4 alkyl, C1, -C4 alkoxy and nitro;
d) quando Y è N(R7),R7 è idrogeno o alchile,n-è 1, R3 è idrogeno ed X è un legame semplice, almeno uno tra R4,R5 ed R6 sia diverso da idrogeno e da OH; d) when Y is N (R7), R7 is hydrogen or alkyl, n-is 1, R3 is hydrogen and X is a simple bond, at least one between R4, R5 and R6 is different from hydrogen and OH;
e loro sali farmaceuticamente accettabili. and pharmaceutically acceptable salts thereof.
I composti di formula I presentano almeno un centro di asimmetria, contrassegnato da un asterisco, e possono essere in forma di stereoisomeri. The compounds of formula I have at least one center of asymmetry, marked by an asterisk, and can be in the form of stereoisomers.
Oggetto della presente invenzione sono i composti di formula I sia sotto forma di miscele stereoisomeriche sia sotto forma d:, singoli stereoisomeri. The object of the present invention are the compounds of formula I both in the form of stereoisomeric mixtures and in the form of single stereoisomers.
I composti di formula I sono agonisti dei recettori dopaminergici attivi anche per via orale e con lunga durata d'azione è sono utili in terapia in campo cardiovascolare, in particolare per il trattamento dell'ipertensione arteriosa e dello scompen-· so cardiaco,dell'insufficienza renale,nel trattamento delle arteropatie periferiche,delle insufficienze cerebrovascolari e della cardiopatia ischemica. The compounds of formula I are dopaminergic receptor agonists active also orally and with a long duration of action and are useful in cardiovascular therapy, in particular for the treatment of arterial hypertension and heart failure, renal insufficiency, in the treatment of peripheral arterial diseases, cerebrovascular insufficiency and ischemic heart disease.
Con il termine atomo di alogeno si intende un atomo di fluoro, cloro, bromo o iodio. The term halogen atom refers to an atom of fluorine, chlorine, bromine or iodine.
Specifici esempi di gruppi alchilici od alcossilici sono Meti-1 le, etile, n.propile, i.propile, n.butile, i.butile, sec.butile, t.butile, metossi, etossi,n.propossi, i.propossi,n.butossi e i.butossi. Specific examples of alkyl or alkoxy groups are Methyl, ethyl, n.propyl, i.propyl, n.butyl, i.butyl, sec.butyl, t.butyl, methoxy, ethoxy, n.propoxy, i.propoxy , n.butoxy and i.butoxy.
Specifici esempi di catene costituite da 3 o 4 gruppi scelti tra CH2, CO, S, 0 ed NH sono i seguenti: -0-CH2-0-, -S-CO-NH-, -CH2-C0-NH-Composti preferiti di formula I sono i composti in cui R’ è un atomo di idrogeno, R ed R" sono gruppi OH e l'atomo di carbonio contrassegnato con un asterisco ha configurazione S. Specific examples of chains consisting of 3 or 4 groups selected from CH2, CO, S, 0 and NH are the following: -0-CH2-0-, -S-CO-NH-, -CH2-C0-NH-Preferred compounds of formula I are the compounds in which R 'is a hydrogen atom, R and R "are OH groups and the carbon atom marked with an asterisk has S configuration.
Composti ancor più preferiti sono i composti in cui R’, R1, ed R2 sono atomi di idrogeno,R ed R" sono gruppi OH, M è 6 e l'atomo di carbonio contrassegnato con un asterisco ha configurazione S. Even more preferred compounds are the compounds in which R ', R1, and R2 are hydrogen atoms, R and R "are OH groups, M is 6 and the carbon atom marked with an asterisk has S configuration.
Tra i significati dei sostituenti preferiti. sono idrogeno, OH,metossi,metile, nitro, cloro, metilsolfonil e metilendiossi. Among the meanings of the preferred substituents. they are hydrogen, OH, methoxy, methyl, nitro, chlorine, methylsulfonyl and methylenedioxy.
Sali farmaceuticamente accettabili dei composti di formula I sono i sali con acidi organici ed inorganici quali, ad esempio, acido cloridrico, bromidrico, iodidrico,.nitrico, solforico, fosforico, acetico, benzoico, maleico, fumarico, succlnicoj tartarico, citrico, aspartico, metansolfonico e 3,7-di-tert.butilnaftalen-1,5-disolfonico (acido dibudinico). Pharmaceutically acceptable salts of the compounds of formula I are salts with organic and inorganic acids such as, for example, hydrochloric, hydrobromic, hydrogen chloride, nitric, sulfuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic and tartaric, citric, aspartic acids, methanesulfonic and 3,7-di-tert.butylnaphthalen-1,5-disulfonic (dibudinic acid).
La preparazióne dei composti di formula I può essere effettuata secondo il metodo di sintesi che viene descritto qui di seguito. The preparation of the compounds of formula I can be carried out according to the synthesis method which is described below.
Il metodo comprende la reazione tra un composto di formula The method comprises the reaction between a compound of formula
in cui in which
sono atomi di idrogeno o gruppi OZ in cui Z è un atomo di idrogeno o un gruppo protettivo scelto,per esempio, tra metile, benzile, benzoile e 4-metossibenzoile, purché almeno uno tra sia un atomo di idrogeno ma non siano tutti contemporaneamente atomi di idrogeno ed non siano ambedue contemporaneamente gruppi OZ; are hydrogen atoms or OZ groups in which Z is a hydrogen atom or a protective group chosen, for example, from methyl, benzyl, benzoyl and 4-methoxybenzoyl, provided that at least one of them is a hydrogen atom but they are not all atoms at the same time hydrogen and not both at the same time OZ groups;
oppure uno tra è un gruppo NHCHO, NHCH3 NHSO2CH3, CH20H o CH» e l’altro è idrogeno; or one of is an NHCHO, NHCH3 NHSO2CH3, CH20H or CH group "and the other is hydrogen;
ed un acido di formula and an acid of formula
in cui ed Y hanno i significati già riportati; W è un gruppo CH2 o CO; Q è un gruppo di formula in which and Y have the meanings already reported; W is a CH2 or CO group; Q is a formula group
in cui R3 ha i significati già riportati,quando o 4; oppure Q è un gruppo in cui R3 ha i significati già riportati, quando n.è 0; in which R3 has the meanings already reported, when or 4; or Q is a group in which R3 has the meanings already reported, when n. is 0;
o un suo derivato reattivo quale un alogenuro acilico o un'anidride mista che possono eventualmente essere preparati in situ, in un solvente inerte ed in presenza di una base quale un carbonato o un bicarbonato alcalino o un’ammina terziaria, ! per ottenere i composti intermedi di formula or a reactive derivative thereof such as an acyl halide or a mixed anhydride which can possibly be prepared in situ, in an inert solvent and in the presence of a base such as an alkaline carbonate or bicarbonate or a tertiary amine,! to obtain the intermediate compounds of formula
hanno i significati già riportati; they have the meanings already reported;
e la loro riduzione, preceduta o seguita dalla eventuale deprotezione dei gruppi ossidrilici. per ottenere i composti di formula I. and their reduction, preceded or followed by the possible deprotection of the hydroxyl groups. to obtain the compounds of formula I.
La riduzione dei composti di formula IV può essere effettuata con agenti riducenti elettrofili, in particolare con diborano eventualmente complessato con dimetilsolfuro, tetraidrofurano ammine alifatiche quali trietilammina o animine aromatiche quali Ν,Ν-dietilanilina o piridina. The reduction of the compounds of formula IV can be carried out with electrophilic reducing agents, in particular with diborane optionally complexed with dimethylsulfide, tetrahydrofuran, aliphatic amines such as triethylamine or aromatic amines such as Ν, Ν-diethylaniline or pyridine.
In alternativa, la riduzione può essere effettuata con agenti riducenti nucleofili quali idruri metallici, per esempio idruro di litio e alluminio. Alternatively, the reduction can be carried out with nucleophilic reducing agents such as metal hydrides, for example lithium and aluminum hydride.
La reazione di riduzione viene effettuata in un opportuno solvente quale ad esempio tetraidrofurano,dietiletere o 1,2-di-! metossietano. The reduction reaction is carried out in a suitable solvent such as for example tetrahydrofuran, diethyl ether or 1,2-di-! methoxyethane.
L’eventuale deprotezione degli ossidrili viene effettuata secondo tecniche convenzionali quali l’idrolisi o l’idrogenolisi.; I composti di formula II sono noti o facilmente preparabil secondo metodi noti (Brevetto inglese n° 1509454 - The Wellcome Foundation Ltd.). Any deprotection of the hydroxyls is carried out according to conventional techniques such as hydrolysis or hydrogenolysis .; The compounds of formula II are known or easily prepared according to known methods (English patent n ° 1509454 - The Wellcome Foundation Ltd.).
Anche i composti di formula III sono noti o sono facilmente preparabili secondo metodi convenzionali. The compounds of formula III are also known or are easily prepared according to conventional methods.
In alternativa, i composti di formula I in cui Y è un gruppo N(R7) possono essere preparati attraverso una diversa sequenza. Dapprima viene effettuata la reazione di condensazione tra un composto di formula II ed un opportuno derivato reattivo di un acido di formula Alternatively, the compounds of formula I in which Y is an N group (R7) can be prepared through a different sequence. First, the condensation reaction is carried out between a compound of formula II and a suitable reactive derivative of an acid of formula
in cui Y è un gruppo N(R7); m ed R7 hanno i significati già riportati; wherein Y is a group N (R7); m and R7 have the meanings already reported;
seguita da eventuale riduzione secondo quanto già riportato, per ottenere l’intermedio di formula followed by any reduction as already reported, to obtain the intermediate formula
in cui Y è un gruppo hanno i significati già riportati. in which Y is a group have the meanings already reported.
L'intermedio di formula VI viene quindi fatto reagire con un opportuno derivato reattivo di un acido di formula The intermediate of formula VI is then reacted with a suitable reactive derivative of an acid of formula
in cui ed X hanno i significati già riportati; in which and X have the meanings already reported;
ottenendo i corrispondenti intermedi di formula IV. obtaining the corresponding intermediates of formula IV.
La successiva riduzione, preceduta o seguita dalla eventuale deprotezione dei gruppi ossidrilici, fornisce i composti di formula I in cui Y è un gruppo N(R7), oggetto della presente invenzione. The subsequent reduction, preceded or followed by the possible deprotection of the hydroxyl groups, gives the compounds of formula I in which Y is an N (R7) group, object of the present invention.
Un ulteriore alternativa per la preparazione dei composti formula I in cui Y è un gruppo N(R7) consiste dapprima nella reazione tra un composto di formula II ed un opportuno derivato reattivo di un acido bicarbossilico di formula A further alternative for the preparation of the compounds formula I in which Y is an N (R7) group consists first of all in the reaction between a compound of formula II and a suitable reactive derivative of a dicarboxylic acid of formula
in cui m-ha i significati già riportati; in which m-has the meanings already reported;
per ottenere un intermedio di formula to get a formula intermediate
in cui hanno i significati già riportati La successiva condensazione con un'ammina di formula in which the meanings already reported have the subsequent condensation with an amine of formula
in cui hanno i significati già riportati; in which they have the meanings already reported;
fornisce i corrispondenti intermedi di formula IV. provides the corresponding intermediates of formula IV.
La successiva riduzione, preceduta o seguita dalla eventuale deprotezione dei gruppi ossidrilici, permette di ottenere i composti di formula I in cui Y è un gruppo N(R7), oggetto della presente invenzione. The subsequent reduction, preceded or followed by the possible deprotection of the hydroxyl groups, allows to obtain the compounds of formula I in which Y is a group N (R7), object of the present invention.
I composti di formula I in forma otticamente attiva vengono ittenuti per separazione ottica o attraverso sintesi stereospecifiche o stereoselettive. The compounds of formula I in optically active form are held by optical separation or by stereospecific or stereoselective synthesis.
La preparazione dei sali del composti di formula I viene effettuata secondo metodi convenzionali. The preparation of the salts of the compound of formula I is carried out according to conventional methods.
I composti dì formula I sono agonisti dei recettori dopaminergici D1 e D2 più affini della dopamina e della dopexamina come risulta dalle prove di binding in vitro (esempio 231. The compounds of formula I are agonists of the dopaminergic receptors D1 and D2 more similar to dopamine and dopexamine as shown by the in vitro binding tests (example 231.
La loro attività è inoltre perlomeno comparabile con quella dei composti descritti nella domanda di brevetto internazionale 93/19036. Furthermore, their activity is at least comparable with that of the compounds described in the international patent application 93/19036.
Le prove di interazione con gli altri sistemi recettoriali hanno mostrato che i composti di formula I non interagiscono significativamente e quindi sono dotati di elevata specificità. I composti di formula I sono risultati anche inattivi sul si stema nervoso centrale per somministrazione orale e tale assenza di effetto è una ulteriore proprietà positiva generalmente non condivìsa dagli altri composti a struttura catecolamminica. The interaction tests with the other receptor systems have shown that the compounds of formula I do not interact significantly and therefore are endowed with high specificity. The compounds of formula I were also found to be inactive on the central nervous system for oral administration and this absence of effect is a further positive property generally not shared by the other compounds with a catecholamine structure.
Appare chiaro come queste caratteristiche di selettività e specificità recettoriale associate alla mancanza di attività sul sistema nervoso centrale rendano i composti di formula I particolarmente adatti per il trattamento di disturbi cardiovascolari e principalmente nella terapia antiipertensiva, nella terapia dello scompenso cardiaco, dell'insufficienza renale, nel trattamento delle arteropatie periferiche, delle insufficienze cerebrovascolari e della cardiopatia ischemica. Oltre alla già sottolineata maggiore attività farmacologica, l'aspetto che caratterizza maggiormente i composti di formula I, oggetto della invenzione è la loro assorbibilità per via orale e la loro prolungata durata d’azione. It is clear how these characteristics of receptor selectivity and specificity associated with the lack of activity on the central nervous system make the compounds of formula I particularly suitable for the treatment of cardiovascular disorders and mainly in antihypertensive therapy, in the therapy of heart failure, renal insufficiency, in the treatment of peripheral arterial diseases, cerebrovascular insufficiency and ischemic heart disease. In addition to the already underlined greater pharmacological activity, the aspect that most characterizes the compounds of formula I, object of the invention is their absorbability orally and their prolonged duration of action.
Ne consegue che per gli impieghi pratici in terapia, i composti di formula I possono essere somministrati sia per via parenterale sia per via enterale a differenza della dopamina e della dopexamina. It follows that for practical uses in therapy, the compounds of formula I can be administered both parenterally and enterally unlike dopamine and dopexamine.
Le dosi terapeutiche saranno generalmente comprese tra 5 mg e 1 g al giorno e tra 1 e 300 mg per via orale per singola somministrazione. Therapeutic doses will generally be between 5 mg and 1 g per day and between 1 and 300 mg orally for single administration.
Costituiscono inoltre oggetto della presente invenzione le composizioni farmaceutiche contenenti un quantitativo terapeuticamente efficace dei composti di formula I o di loro salii farmaceuticamente accettabili in miscela con un adatto veicolante. The pharmaceutical compositions containing a therapeutically effective quantity of the compounds of formula I or of their pharmaceutically acceptable salts in admixture with a suitable carrier are also object of the present invention.
Le composizioni farmaceutiche oggetto dell’invenzione possono essere liquide, adatte alla somministrazione enterale o parenterale, e, preferibilmente, solide quali compresse, capsule, granulati, adatte per la somministrazione orale. The pharmaceutical compositions object of the invention can be liquid, suitable for enteral or parenteral administration, and, preferably, solid such as tablets, capsules, granulates, suitable for oral administration.
La preparazione delle composizioni farmaceutiche oggetto della invenzione può essere effettuata secondo tecniche tradizionali. Malgrado i composti di formula I siano attivi come tali anche quando somministrati oralmente, per soddisfare alcune specifiche esigenze terapeutiche o farmaceutiche può essere utile trasformarli in corrispondenti pro-drugs. The preparation of the pharmaceutical compositions object of the invention can be carried out according to traditional techniques. Although the compounds of formula I are active as such even when administered orally, to meet some specific therapeutic or pharmaceutical needs it may be useful to transform them into corresponding pro-drugs.
Secondo le tecniche in uso nel settore dei derivati fenolici e catecolici, adatti pro-drugs si ottengono per esterificazione di uno o due ossidrili con acidi farmaceuticamente accettabili. Esempi specifici di pro-drugs dei composti di formula I sono gli acetossi derivati, in cui gli ossidrili-sono esterificati con acido acetico, e i mono- o di-fosfonati, in cui uno o en-« trambi gli ossidrili sono esterificati con acido fosforico. According to the techniques used in the sector of phenolic and catechol derivatives, suitable pro-drugs are obtained by esterification of one or two hydroxyls with pharmaceutically acceptable acids. Specific examples of pro-drugs of the compounds of formula I are the acetoxy derivatives, in which the hydroxyls are esterified with acetic acid, and the mono- or di-phosphonates, in which one or both hydroxyls are esterified with phosphoric acid. .
Rientrano nello spirito della presente invenzione i composti di formula I anche quando trasformati in pro-drugs ed in particolare i composti ottenuti per esterificazione degli ossidrili fenolici o di uno o ambedue gli ossidrili catecolici con acidi farmaceuticamente accettabili, nonché le composizioni farmaceutiche che contengono un composto di formula I sotto forma di un corrispondente pro-drug, ed in particolare che contengono un composto di formula I in cui gli ossidrili fenolici o uno o ambedue gli ossidrili catecolici sono stati esterificati con acidi farmaceuticamente accettabili. The compounds of formula I fall within the spirit of the present invention even when transformed into pro-drugs and in particular the compounds obtained by esterification of the phenolic hydroxyls or of one or both of the catechol hydroxyls with pharmaceutically acceptable acids, as well as the pharmaceutical compositions which contain a compound of formula I in the form of a corresponding pro-drug, and in particular containing a compound of formula I in which the phenolic hydroxyls or one or both of the catechol hydroxyls have been esterified with pharmaceutically acceptable acids.
Allo scopo di meglio illustrare la presente invenzione vengono ora forniti i seguenti esempi. In order to better illustrate the present invention, the following examples are now provided.
Le purificazioni cromatografiche sono state effettuate su colonne di gel di silice (230-400 mesh). The chromatographic purifications were performed on silica gel columns (230-400 mesh).
Gli spettri di massa, qualora non diversamente specificato, sono stati effettuati nelle seguenti condizioni: ionizzazione chimica, isobutano, ioni positivi. The mass spectra, unless otherwise specified, were carried out under the following conditions: chemical ionization, isobutane, positive ions.
Esempio 1 Example 1
Preparazione-di- acido- 6-[(4-metossifeniltio)acetilamminolesanoico (Intermedio 1). Preparation-of- 6 - [(4-methoxyphenylthio) acetylaminolesanoic acid (Intermediate 1).
Ad una soluzione di acido (4-metossifeniltio)acetico (2 g; 10,1 mmoli) in cloruro di metilene (20 ml) sono stati aggiunti sotto agitazione a temperatura ambiente N,N-dimetilformammide (50 μl) e cloruro di tionile (1,8 g; 15,1 mmoli). N, N-dimethylformamide (50 μl) and thionyl chloride ( 1.8 g; 15.1 mmol).
Dopo 1 ora il solvente è stato evaporato a pressione ridotta e l’olio ottenuto è stato sciolto in cloruro di metilene (3 mi). La soluzione così ottenuta e, contemporaneamente,una soluzione di idrossido di sodio 4N (3 mi) sono state aggiunte per goccio-j lamento sotto vigorosa agitazione ad una soluzione di acidoj 6-amminoesanoico (1,3 g; 9,9 mmoli) ed idrossido di sodio (0,4 g; 10 mmoli) in acqua (5 mi). After 1 hour the solvent was evaporated under reduced pressure and the oil obtained was dissolved in methylene chloride (3 ml). The solution thus obtained and, at the same time, a 4N sodium hydroxide solution (3 ml) were added by dropping under vigorous stirring to a solution of 6-aminohexanoic acid (1.3 g; 9.9 mmoles) and sodium hydroxide (0.4 g; 10 mmol) in water (5 ml).
La miscela di reazione è stata mantenuta sotto agitazione a temperatura ambiente per 2 ore. The reaction mixture was kept under stirring at room temperature for 2 hours.
Dopo separazione delle fasi, la fase acquosa è stata lavata con cloruro di metilene (5 mi), acidificata con HCl 37% fino a pH 1 e quindi estratta con cloruro di metilene (20 mi). After separation of the phases, the aqueous phase was washed with methylene chloride (5 ml), acidified with 37% HCl to pH 1 and then extracted with methylene chloride (20 ml).
La fase organica è stata anidrificata su solfato di sodio anidro. The organic phase was dried over anhydrous sodium sulfate.
Dopo raffreddamento a 0°C e filtrazione del solido formatosi, è stato ottenuto Intermedio 1 (2,4 g). After cooling to 0 ° C and filtration of the solid formed, Intermediate 1 (2.4 g) was obtained.
H-NMR (200 MHz;DMS0-d6): 6 (ppm): 1,15-1,62 (m, 6H); 2,15 (t. H-NMR (200 MHz; DMS0-d6): 6 (ppm): 1.15-1.62 (m, 6H); 2.15 (t.
Operando in maniera analoga sono stati preparati'i seguenti. composti. Operating in a similar way, the following have been prepared. compounds.
Acido_ 6-[(4-fenilmetossifenossi)acetilamminolesanoico (Intermedio 2) Acid_ 6 - [(4-phenylmethoxyphenoxy) acetylaminolesanoic (Intermediate 2)
Acido 6-13-(4-metossifenilipropionilamininolesanoico (Intermedio 3) 6-13- (4-methoxyphenylipropionylamininolesanoic acid (Intermediate 3)
Acido 6--(3.4-metilendiossifenil)acetilaminino]esanoico (Intermedio 4) 6 - (3.4-methylenedioxyphenyl) acetylaminino] hexanoic acid (Intermediate 4)
Acido 6-[1 .4-benzodiossan-2-il)carbonilamminolesanoico (Intermedio 5) 6- [1 .4-benzodioxane-2-yl) carbonylaminolesanoic acid (Intermediate 5)
Massa: 344 [M+1]. Mass: 344 [M + 1].
Esempio 2 Example 2
Preparazione di acido 6-(6.7-dimetossi-1.2.3.4-tetraldro-isochinolin-2-il)-6-cheto-esanoico (Intermedio 10) Preparation of 6- (6.7-dimethoxy-1.2.3.4-tetralder-isoquinolin-2-yl) -6-keto-hexanoic acid (Intermediate 10)
Ad una soluzione di 6,7-dimetossi-1,2,3,4-tetraidroisochinolina cloridrato (3,1 g; 13,5 mmoli) e trietilammina (3,7 g; 37,1 mmoli) in cloruro di metilene (50 mi) è stata aggiunta, sotto agitazione a temperatura ambiente, una soluzione di cloruro dell'acido esandioico monometilestere (3,6 g; 20,2 mmoli) in cloruro di metilene (10 ml) To a solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.1 g; 13.5 mmol) and triethylamine (3.7 g; 37.1 mmol) in methylene chloride (50 ml) a solution of hexanioic acid monomethylester chloride (3.6 g; 20.2 mmoles) in methylene chloride (10 ml) was added under stirring at room temperature
Dopo 2 ore è stata aggiunta acqua (50 mi) e le fasi sono state separate. After 2 hours, water (50 ml) was added and the phases were separated.
La fase organica è stata lavata con una soluzione acquosa di HC1 0,2N e quindi con una soluzione satura di cloruro di sodio.I Dopo anidrificazione su solfato di sodio anidro ed evaporazione a secchezza a pressione ridotta, il residuo è stato sciolto in metanolo (10 ml). The organic phase was washed with an aqueous solution of 0.2N HC1 and then with a saturated solution of sodium chloride. I After anhydrification on anhydrous sodium sulphate and evaporation to dryness under reduced pressure, the residue was dissolved in methanol ( 10 ml).
Alla soluzione risultante è stata aggiunta goccia a goccia, sotto agitazione a temperatura ambiente, una soluzione di idrossido di sodio (1,1 g; 27,5 amoli) in acqua (5 mi) e la miscela di reazione è stata mantenuta sotto agitazione per 2 ore. To the resulting solution a solution of sodium hydroxide (1.1 g; 27.5 amol) in water (5 ml) was added drop by drop, under stirring at room temperature, and the reaction mixture was kept under stirring for 2 hours.
Dopo evaporazione del metanolo a pressione ridotta, sono stati aggiunti acqua (10 mi), cloruro di metilene (20 mi) ed HCl 37% fino a pH 1. After evaporation of the methanol under reduced pressure, water (10 ml), methylene chloride (20 ml) and 37% HCl were added up to pH 1.
Dopo separazione delle fasi, la fase acquosa è stata nuovamente estratta con cloruro di metilene (20 ml). After separation of the phases, the aqueous phase was again extracted with methylene chloride (20 ml).
Le fasi organiche riunite sono state anidrificate su solfato di sodio anidro ottenendo, dopo evaporazione del solvente, Intermedio 10 (3,6 g) come olio. The combined organic phases were dried over anhydrous sodium sulphate obtaining, after evaporation of the solvent, Intermediate 10 (3.6 g) as oil.
Operando in maniera analoga è stato preparato il seguente composto. By operating in a similar manner the following compound was prepared.
Esempio 3 Example 3
Preparazione- di- acido 6-[2-[3.4-di(fenilmetossi)fenilletossilesanoico (Intermedio 12) Preparation- di- 6- [2- [3.4-di (phenylmethoxy) phenyl ethoxyhexanoic acid (Intermediate 12)
Ad una soluzione di 2-[3,4-di(fenilmetossi)fenil]etanolo (9 g; 26,9 mmoli) e 1,5-dibromopentano (12,4 g; 53,9 mmoli) in tetraidrofurano (200 mi) e N.N-dimetilformammide (20 mi) è stato aggiunto, sotto azoto a temperatura ambiente, idruro di sodio (0,7 g; 29,2 mmoli). To a solution of 2- [3,4-di (phenylmethoxy) phenyl] ethanol (9 g; 26.9 mmol) and 1,5-dibromopentane (12.4 g; 53.9 mmol) in tetrahydrofuran (200 ml) and N.N-dimethylformamide (20 ml) sodium hydride (0.7 g; 29.2 mmol) was added under nitrogen at room temperature.
La miscela di reazione è stata scaldata a riflusso sotto agitazione per 5 ore e quindi versata in acido cloridrico acquoso 1N (500 ml). The reaction mixture was refluxed under stirring for 5 hours and then poured into 1N aqueous hydrochloric acid (500 ml).
Dopo estrazione con etere etilico (2x200 ml), la fase After extraction with ethyl ether (2x200 ml), the
è stata lavata con acqua, anidrificata su solfato di sodio anidro e portata a secchezza a pressione ridotta. it was washed with water, dried over anhydrous sodium sulphate and brought to dryness under reduced pressure.
Il grezzo è stato purificato per cromatografia (eluente etere di petrolio:acetato d'etile=75:25) ottenendo 5-bromopentil-2-[3,4-dl(fenilmetossi)fenil]etil-etere (4 g) come olio . The crude was purified by chromatography (eluent petroleum ether: ethyl acetate = 75: 25) obtaining 5-bromopentyl-2- [3,4-dl (phenylmethoxy) phenyl] ethyl ether (4 g) as oil.
Iodio (20 mg) e, dopo 10 minuti,per gocciolamento una soluzione di 5-bromopentil-2-[3,4-di(fenilmetossi)fenil]etil-etere (3,8 g; 7,9 mmoli) in tetraidrofurano (25 mi) sono stati aggiunti ad una sospensione di magnesio in trucioli (0,2 g; 8,3 mmoli) in tetraidrofurano (5 ml), sotto azoto a temperatura ambiente. Iodine (20 mg) and, after 10 minutes, by dropping a solution of 5-bromopentyl-2- [3,4-di (phenylmethoxy) phenyl] ethyl-ether (3.8 g; 7.9 mmol) in tetrahydrofuran ( 25 ml) was added to a slurry of magnesium chips (0.2 g; 8.3 mmol) in tetrahydrofuran (5 ml), under nitrogen at room temperature.
La miscela di reazione è stata scaldata a riflusso per 5 ore, quindi raffreddata a temperatura ambiente e versata in un pal Ione contenente ghiaccio secco. The reaction mixture was refluxed for 5 hours, then cooled to room temperature and poured into a bucket containing dry ice.
Dopo riscaldamento a temperatura ambiente, sono stati aggiunti etere etilico ed acido cloridrico acquoso 1N. After heating to room temperature, ethyl ether and 1N aqueous hydrochloric acid were added.
Le fasi sono state separate e la fase organica è stata anidrificata su solfato di sodio anidro. The phases were separated and the organic phase was dried over anhydrous sodium sulfate.
Dopo evaporazione a secchezza a pressione ridotta, il grezzo è stato purificato per cromatografia (eluente After evaporation to dryness under reduced pressure, the crude was purified by chromatography (eluent
Esempio 4 Example 4
Preparazione di 1-(4-metossifenilmetil)piperazina (Intermedio 13) Preparation of 1- (4-methoxyphenylmethyl) piperazine (Intermediate 13)
Ad una soluzione di piperazina (21,5 g; 250 mmoli), trietilamraina (3 g; 30 mmoli) e ioduro di potassio ( 4,1 g; 25 mmoli) in N,N-dimetilformammide (150 mi) è stato aggiunto 4-metossifenilmetilcloruro (3,9 g;25 mmoli). To a solution of piperazine (21.5 g; 250 mmol), triethylamraine (3 g; 30 mmol) and potassium iodide (4.1 g; 25 mmol) in N, N-dimethylformamide (150 ml) was added 4 -methoxyphenylmethyl chloride (3.9 g; 25 mmoles).
Dopo 5 ore la miscela di reazione è stata versata in acqua ed estratta 3 volte con etere etilico. After 5 hours the reaction mixture was poured into water and extracted 3 times with ethyl ether.
La fase acquosa è stata concentrata a piccolo volume evaporando i solventi a pressione ridotta e nuovamente estratta 3 volte con etere etilico. The aqueous phase was concentrated to a small volume by evaporating the solvents under reduced pressure and again extracted 3 times with ethyl ether.
Le fasi organiche sono state riunite alle precedenti, anidrificate su solfato di sodio anidro ed evaporate a secchezza a pressione ridotta. The organic phases were combined with the previous ones, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure.
Il grezzo è stato purificato per cromatografia (eluente The crude was purified by chromatography (eluent
Esempio 5 Example 5
Preparazione di t.butildimetilsililestere dell'acido (3-cloro-4-t.batildimetilsllilossi)fenilacetico (Intermedio 14) Preparation of t.butyldimethylsilyl ester of (3-chloro-4-t.bathyldimethylsilyloxy) phenylacetic acid (Intermediate 14)
Ad una soluzione di acido (3-cloro-4-idrossi)fenilacetico (1 g; 5,3 mmoli) e di t.butildimetilsililcloruro (2 g; 13,3 mmoli) in N,N-dimetilformammide (6 mi) è stato aggiunto imidazolo (1,8 g; 26,4 mmoli), sotto azoto a temperatura ambiente. To a solution of (3-chloro-4-hydroxy) phenylacetic acid (1 g; 5.3 mmol) and t.butyldimethylsilyl chloride (2 g; 13.3 mmol) in N, N-dimethylformamide (6 ml) was added imidazole (1.8 g; 26.4 mmoles), under nitrogen at room temperature.
La miscela di reazione è stata mantenuta sotto agitazione a temperatura ambiente per 5 ore,quindi versata in una soluzione acquosa di bicarbonato di sodio 5% (25 mi) ed estratta con esano (2x30 mi). The reaction mixture was kept under stirring at room temperature for 5 hours, then poured into a 5% aqueous solution of sodium bicarbonate (25 ml) and extracted with hexane (2x30 ml).
La fase organica è stata anidrificata su solfato di sodio anidro ed il solvente è stato evaporato a pressione ridotta ottenendo Intermedio 14 (2,2 g) come olio. The organic phase was dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure to obtain Intermediate 14 (2.2 g) as oil.
Operando in maniera analoga sono stati preparati i seguenti composti. Operating in a similar manner, the following compounds were prepared.
t.Butildimetilsililestere dell 'acido (3-nitro-4-t.butildimetilsililossi ) fenilacetico (Intermedio 15) t.Butyldimethylsilyl ester (3-nitro-4-t.butyldimethylsilyloxy) phenylacetic acid (Intermediate 15)
t.Butildimetilsililestere dell 'acido ( 3-metossi-4-t.butildimetilsilllossi)fenilacetico (Intermedio 16) t.Butyldimethylsilyl ester (3-methoxy-4-t.butyldimethylsyloxy) phenylacetic acid (Intermediate 16)
Esempio 6 Example 6
Preparazione di (S)-N-propil-N-[(6-ammino-1-oxo)esill-5.6-dimetossi-1.2.3.4-tetraidro-2-naftilammina (Intermedio 17) Preparation of (S) -N-propyl-N - [(6-amino-1-oxo) hexyl-5.6-dimethoxy-1.2.3.4-tetrahydro-2-naphthylamine (Intermediate 17)
Ad una sospensione di (S)-N-propil-5,6-dimetossi-l,2,3,4-tetraidro-2-naftilammina cloridrato (14,4 g; 50,4 mmoli) in cloruro di metilene (150 mi),mantenuta sotto agitazione a temperatura ambiente, sono stati aggiunti trietilammina (12,7 g; 126,1 mmoli) e quindi una soluzione di cloruro dell'acido 6-ftalimmidoesanoico (15,5 g; 55,5 mmoli) in cloruro di metilene (12Ò mi). To a suspension of (S) -N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (14,4 g; 50,4 mmol) in methylene chloride (150 ml ), kept under stirring at room temperature, were added triethylamine (12.7 g; 126.1 mmoles) and then a solution of 6-phthalimidohexanoic acid chloride (15.5 g; 55.5 mmoles) in chloride of methylene (12Òml).
La miscela di reazione è stata mantenuta sotto agitazione a temperatura ambiente per 1,5 ore. The reaction mixture was kept under stirring at room temperature for 1.5 hours.
Dopo aggiunte di acqua (250 ml) e separazione delle fasi, la fase organica è stata lavata con acqua (150 ml), anidrificata su solfato di sodio anidro ed il solvente è stato evaporato a pressione ridotta. After addition of water (250 ml) and separation of the phases, the organic phase was washed with water (150 ml), dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure.
Il residuo è stato purificato per cromatografia (eluente etere The residue was purified by chromatography (eluent ether
Una soluzione di (S)-N-propil-N-[(6-ftalimmido-1-oxo)esil]-5,6--dimetossi-1,2,3,4-tetraidro-2-naftilammina (24,1 g; 48,9 mmo li) in metilammina etanolica 33% (240 mi) è stata mantenuta sotto agitazione a temperatura ambiente per 20 ore. A solution of (S) -N-propyl-N - [(6-phthalimido-1-oxo) hexyl] -5,6 - dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine (24,1 g; 48.9 ml) in 33% ethanolic methylamine (240 ml) was kept under stirring at room temperature for 20 hours.
La miscela di reazione è stata portata a secchezza a pressione ridotta ed il resìduo è stato purificato per cromatografia (eluente cloruro di metilene:metanolo:ammoniaca 30X=90:10:1) ottenendo Intermedio 17 (11,9 g) come olio. The reaction mixture was brought to dryness under reduced pressure and the residue was purified by chromatography (eluent methylene chloride: methanol: ammonia 30X = 90: 10: 1) obtaining Intermediate 17 (11.9 g) as oil.
Esempio 7 Example 7
Preparazione di_ (5)-Ν-propil-N-[(6-ammino)esill-5.6-dimetossi-1.2.3,4-tetraidro-2-naftilammina dicloridrato (Intermedio 18) Ad una soluzione di Intermedio 17 (2,3 g; 6,34 mmoli),preparato come descritto nell'esempio 6, in tetraidrofurano (40 ml) è! stato aggiunto lentamente a temperatura ambiente, sotto agitazione e sotto azoto, complesso borano-dimetilsolfuro (3 g; 37 nutoli). Preparation of_ (5) -Ν-propyl-N - [(6-amino) hexyl-5.6-dimethoxy-1.2.3,4-tetrahydro-2-naphthylamine dihydrochloride (Intermediate 18) to a solution of Intermediate 17 (2,3 g; 6.34 mmol), prepared as described in Example 6, in tetrahydrofuran (40 ml) is! borane-dimethyl sulfide complex (3 g; 37 nutoles) was added slowly at room temperature, under stirring and under nitrogen.
Al termine dell'aggiunta la miscela di reazione è stata scaldata a riflusso per 2 ore. At the end of the addition the reaction mixture was heated under reflux for 2 hours.
Dopo raffreddamento a 5°C è stata aggiunta una soluzione di acido cloridrico 37% (1,5 mi) in metanolo (12 ml). After cooling to 5 ° C, a solution of 37% hydrochloric acid (1.5 ml) in methanol (12 ml) was added.
La miscela di reazione è stata nuovamente scaldata a riflusso per 1 ora,quindi concentrata distillando i solventi a pressione atmosferica e portando a secchezza a pressione ridotta. The reaction mixture was again heated under reflux for 1 hour, then concentrated by distilling the solvents at atmospheric pressure and bringing to dryness at reduced pressure.
Il residuo è stato sciolto in metanolo (30 mi) ed il solvente distillato a pressione ridotta; è stato aggiunto nuovamente metanolo (30 mi) ed il solvente è stato evaporato a secchezza. Il grezzo è stato purificato per cromatografia (eluente The residue was dissolved in methanol (30 ml) and the solvent distilled under reduced pressure; methanol (30 ml) was added again and the solvent was evaporated to dryness. The crude was purified by chromatography (eluent
Il solido ottenuto è stato sciolto in etanolo assoluto ed è stata aggiunta una soluzione di acido cloridrico in etere etilico (15% p/v) fino a pH nettamente acido. The solid obtained was dissolved in absolute ethanol and a solution of hydrochloric acid in ethyl ether (15% w / v) was added up to a clearly acidic pH.
Per evaporazione dei solventi a pressione ridotta è stato ottenuto Intermedio 18 (1,9 g) come solido bianco amorfo. By evaporation of the solvents under reduced pressure, Intermediate 18 (1.9 g) was obtained as a white amorphous solid.
Esempio 8 Example 8
Preparazione di_ (S)-N-propil-N-[(6-ammino)esil]-5.6-diidrossi-1.2.3.4-tetraidro-2-naftilamraina dibromidrato (Intermedio 19) Una soluzione di Intermedio 18 (1,2 g; 2,87 rantoli), preparato come descritto nell'esempio 7, in acido bromidrico 48% (10 ml) è stata scaldata a riflusso sotto azoto per 5 ore. Preparation of_ (S) -N-propyl-N - [(6-amino) hexyl] -5.6-dihydroxy-1.2.3.4-tetrahydro-2-naphthylamraine dibromide (Intermediate 19) A solution of Intermediate 18 (1.2 g; 2.87 rales), prepared as described in example 7, in 48% hydrobromic acid (10 ml) was heated under reflux under nitrogen for 5 hours.
La miscela di reazione è stata quindi portata a secchezza a pressione ridotta ed al residuo cosi ottenuto è stato aggiunto etanolo assoluto (20 mi). The reaction mixture was then brought to dryness under reduced pressure and absolute ethanol (20 ml) was added to the residue thus obtained.
Dopo evaporazione del solvente, è stato aggiunto acetato d'etile (20 mi) ed il solvente è stato nuovamente evaporato. After evaporation of the solvent, ethyl acetate (20 ml) was added and the solvent was again evaporated.
Il grezzo risultante è stato purificato per cristallizzazione da una miscela etanolo assoluto/acetato d'etile ottenendo Intermedio 19 (1,2 g) come solido bianco. The resulting crude was purified by crystallization from an absolute ethanol / ethyl acetate mixture obtaining Intermediate 19 (1.2 g) as a white solid.
Esempio 9 Example 9
Ad una soluzione di (S)-N-propil-5,6-diidrossi-1,2,3,4-tetraidro-2-naftilammina bromidrato (20 g; 66 mmoli) e trietilammina (6,7 g; 66 mmoli) in N,N-dimetilformammide (160 ml) è stata aggiunta sotto agitazione,a temperatura ambiente e sotto azoto, una soluzione di di-t.butildicarbonato (14,5 g; 66,2 mmoli) in N,N-dimetilformammide (28 mi). To a solution of (S) -N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine hydrobromide (20 g; 66 mmol) and triethylamine (6.7 g; 66 mmol) in N, N-dimethylformamide (160 ml), a solution of di-t.butyldicarbonate (14.5 g; 66.2 mmoles) in N, N-dimethylformamide (28 me).
La miscela di reazione è stata mantenuta sotto agitazione per 3 ore, quindi versata in una miscela di acqua, ghiaccio ed etere etilico. The reaction mixture was kept under stirring for 3 hours, then poured into a mixture of water, ice and ethyl ether.
Dopo aggiunta di HC1 -1N fino a pH nettamente acido, le fasi sono state separate. After addition of -1N HCl up to a clearly acidic pH, the phases were separated.
La fase organica è stata lavata 2 volte con acqua, anidrificata su solfato di sodio anidro ed evaporata a secchezza a pressione ridotta. The organic phase was washed twice with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure.
Il residuo è stato sciolto in N,N-dimetilformammide (250 mi) ec alla soluzione ottenuta sono stati aggiunti, sotto agitazione a temperatura ambiente, carbonato di potassio (34,4 g; 248,9 mmoli) e bromuro di benzile (26,6 g; 155,5-mmoli). The residue was dissolved in N, N-dimethylformamide (250 ml) and potassium carbonate (34.4 g; 248.9 mmoles) and benzyl bromide (26, 6 g; 155.5-mmol).
La miscela di reazione è stata scaldata a 60°C per 7 ore, poi mantenuta sotto agitazione a temperatura ambiente per 16 ore ed infine versata in una miscela di acqua ed etere etilico. The reaction mixture was heated at 60 ° C for 7 hours, then kept under stirring at room temperature for 16 hours and finally poured into a mixture of water and ethyl ether.
Dopo separazione delle fasi, la fase organica è stata lavata con acqua,anidrificata su solfato di sodio anidro ed il solvente evaporato a pressione ridotta. After separation of the phases, the organic phase was washed with water, dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure.
Il residuo è stato purificato per cromatografia (eluente etere di petrolio:acetato d’etile=93:7) ottenendo (S)-N-t.butossicarbonil-N-propil-5,6-di(fenilmetossi)-1,2,3,4-tetraidro-2-naftilammina (23 g) come olio. The residue was purified by chromatography (eluent petroleum ether: ethyl acetate = 93: 7) to obtain (S) -N-t.butoxycarbonyl-N-propyl-5,6-di (phenylmethoxy) -1,2,3, 4-tetrahydro-2-naphthylamine (23 g) as oil.
Ad una soluzione di (S)-N-t.butossicarbonil-N-propil-5,6-di-(fenilmetossi)-1,2,3,4-tetraidro-2-naftilammina (23 g; 45,8 mmoli) in acetato d'etile (100 mi) è stata aggiunta, sotto agitazione a temperatura ambiente,una soluzione di acido clo ridrico in acetato d'etile (13% p/v) (250 mi). To a solution of (S) -N-t.butoxycarbonyl-N-propyl-5,6-di- (phenylmethoxy) -1,2,3,4-tetrahydro-2-naphthylamine (23 g; 45.8 mmoles) in acetate of ethyl (100 ml) a solution of hydrochloric acid in ethyl acetate (13% w / v) (250 ml) was added under stirring at room temperature.
Dopo 30 minuti il precipitato è stato filtrato, lavato con acetato d'etile e seccato sotto vuoto a 50°C per 10 ore, otte nendo (S)-N-propil-5,6-di(fenilmetossi)-1,2,3,4-tetraidro-2 naftilammina cloridrato (16,4 g;) come solido bianco. After 30 minutes the precipitate was filtered, washed with ethyl acetate and dried under vacuum at 50 ° C for 10 hours, obtaining (S) -N-propyl-5,6-di (phenylmethoxy) -1,2, 3,4-tetrahydro-2 naphthylamine hydrochloride (16.4 g;) as a white solid.
Ad una soluzione di (S)-N-propil-5,6-di(fenilmetossi)-i,2,3,4 tetraidro-2-naftilammina cloridrato (16 g; 36,5 mmoli) e trietilammina (9,2 g; 91,3 mmoli) in cloruro di metilene (130 mi) mantenuta sotto agitazione a temperatura ambiente, è stata aggiunta una soluzione di cloruro dell'acido 6-ftalimmidoesanoico (11,2 g; 40,2 mmoli) in cloruro di metilene (60 mi). To a solution of (S) -N-propyl-5,6-di (phenylmethoxy) -i, 2,3,4 tetrahydro-2-naphthylamine hydrochloride (16 g; 36,5 mmol) and triethylamine (9,2 g ; 91.3 mmol) in methylene chloride (130 ml) kept under stirring at room temperature, a solution of 6-phthalimidohexanoic acid chloride (11.2 g; 40.2 mmol) in methylene chloride ( 60 ml).
La miscela di reazione è stata mantenuta sotto agitazione a temperatura ambiente per 1 ora. The reaction mixture was kept under stirring at room temperature for 1 hour.
Dopo aggiunta di acqua e separazione delle fasi, la fase orgenica è stata lavata con acqua (100 ml), anidrificata su solfato di sodio anidro ed il solvente è stato evaporato a pressione ridotta. After addition of water and separation of the phases, the orgenic phase was washed with water (100 ml), dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure.
Il residuo è stato sciolto in una soluzione di metilammina etanolica 33% (240 ml) e la miscela di reazione è stata mantenuta sotto agitazione a temperatura ambiente per 6 ore. The residue was dissolved in a 33% ethanolic methylamine solution (240 ml) and the reaction mixture was stirred at room temperature for 6 hours.
Dopo evaporazione del solvente a pressione ridotta, il residuo è stato purificato per cromatografia (eluente After evaporation of the solvent under reduced pressure, the residue was purified by chromatography (eluent
moniaca 30%=90:10:1) ottenendo Intermedio 20 (10,9 g). moniac 30% = 90: 10: 1) obtaining Intermediate 20 (10.9 g).
Esempio 10 Example 10
Preparazione_ di (3)-N-propil-N-(5,6-dimetossi-1,2.3.4-tetraidro-2-naftil)-6-carbossi-esanammide (Intermedio 21) Preparation_ of (3) -N-propyl-N- (5,6-dimethoxy-1,2.3.4-tetrahydro-2-naphthyl) -6-carboxy-hexanamide (Intermediate 21)
Ad una soluzione di (S)-N-propil-5,6-dimetossi-1,2,3,4-tetraidro-2-naftilammina bromidrato (10 g; 30,3 mmoli) e trietilammina (7,6 g; 75,3 mmoli) in cloruro di metilene (80 mi) è stata aggiunta, sotto agitazione a temperatura ambiente, una| soluzione di cloruro dell'acido esandioico monometilestere (5,9| g; 33,3 mmoli) in cloruro di metilene (10 ml). To a solution of (S) -N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrobromide (10 g; 30.3 mmol) and triethylamine (7.6 g; 75 , 3 mmol) in methylene chloride (80 ml) was added, under stirring at room temperature, a | chloride solution of monomethyl ester hexanioic acid (5.9 | g; 33.3 mmol) in methylene chloride (10 ml).
Dopo 2 ore è stata aggiunta acqua (100 ml) e le fasi sono state separate. After 2 hours, water (100 ml) was added and the phases were separated.
La fase organica è stata lavata con una soluzione acquosa di HCl 0,2N,quindi con acqua, anidrificata su solfato di sodioj anidro ed evaporata a secchezza a pressione ridotta. The organic phase was washed with an aqueous solution of 0.2N HCl, then with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure.
Il residuo è stato sciolto in metanolo (50 mi) ed alla soluzio-j ne cosi ottenuta è stata aggiunta goccia a goccia, sotto agita-j zione a temperatura ambiente, una soluzione di NaOH (3,3 g; 82,5 mmoli) in acqua (17 mi). The residue was dissolved in methanol (50 ml) and a solution of NaOH (3.3 g; 82.5 mmoles) was added drop by drop, under stirring at room temperature, to the solution thus obtained. in water (17 mi).
La miscela di reazione è stata mantenuta sotto agitazione per 3 ore The reaction mixture was kept under stirring for 3 hours
Dopo evaporazione dei solventi a pressione ridotta, il residuo è stato sciolto in acqua (40 mi). After evaporation of the solvents under reduced pressure, the residue was dissolved in water (40 ml).
La soluzione è stata lavata con etere etilico (40 mi), quindi acidificata con acido cloridrico 373⁄4 fino a pH 1 ed estratta con cloruro di metilene (100 mi). The solution was washed with ethyl ether (40 ml), then acidified with 373⁄4 hydrochloric acid to pH 1 and extracted with methylene chloride (100 ml).
Dopo anidrificazione della fase organica su solfato di sodio anidro ed evaporazione del solvente, è stato ottenuto Intermedio 21 (11,4 g) come olio. After drying the organic phase over anhydrous sodium sulfate and evaporating the solvent, Intermediate 21 (11.4 g) was obtained as an oil.
6,69 (d, 1H) ; 6,79 (d, 1H) . 6.69 (d, 1H); 6.79 (d, 1H).
Nassa: 378 [M+1 ] . Keepnet: 378 [M + 1].
Esempio 11 Example 11
Preparazione di (S)-N-propil-N-[6-[2-(4-metosslfeniltio)etilannoino! esili -5.6-dimetossi-1 .2.3.4-tetraidro-2-naftilanmiina dicloridrato (Composto A) Preparation of (S) -N-propyl-N- [6- [2- (4-methoxyphenylthio) ethylannoino! hexyls -5.6-dimethoxy-1 .2.3.4-tetrahydro-2-naphthylanmiine dihydrochloride (Compound A)
Ad una sospensione di Intermedio 1 (2,4 g; 7,7 mmoli), prepara to come descritto nell’esempio 1, in cloruro di metilene (20 mi! è stato aggiunto cloruro di tionile (1,4 g; 11,7 mmoli), sotto agitazione a temperatura ambiente. To a suspension of Intermediate 1 (2.4 g; 7.7 mmoles), prepared as described in Example 1, in methylene chloride (20 ml) thionyl chloride (1.4 g; 11.7 mmoles), under stirring at room temperature.
Dopo 1 ora il solvente è stato evaporato a pressione ridotta' ottenendo un olio che è stato sciolto in cloruro di metilene (10 mi). After 1 hour the solvent was evaporated under reduced pressure obtaining an oil which was dissolved in methylene chloride (10 ml).
La soluzione è stata aggiunta per gocciolamento ad una sospensione ottenuta aggiungendo trietilammina (2,1 g; 21 mmoli), sotto agitazione a temperatura ambiente, ad una sospensione di (S)-N-propil-5,6-dimetossi-1,2,3,4-tetraidro-2-naftilammina bromidrato (2,3 g; 7 mmoli) in cloruro di metilene (30 mi). La miscela di reazione è stata mantenuta sotto agitazione a temperatura ambiente per 1 ora. The solution was added dropwise to a suspension obtained by adding triethylamine (2.1 g; 21 mmoles), under stirring at room temperature, to a suspension of (S) -N-propyl-5,6-dimethoxy-1,2 , 3,4-tetrahydro-2-naphthylamine hydrobromide (2.3 g; 7 mmol) in methylene chloride (30 ml). The reaction mixture was kept under stirring at room temperature for 1 hour.
Dopo aggiunta di acqua (40 mi) e separazione delle fasi, la fase organica è stata lavata con acqua acida, anidrificata su solfato di sodio anidro e portata a secchezza a pressione ridotta. After addition of water (40 ml) and separation of the phases, the organic phase was washed with acidic water, dried over anhydrous sodium sulphate and brought to dryness under reduced pressure.
Il residuo è stato sciolto sotto azoto in tetraidrofurano (20 mi). The residue was dissolved under nitrogen in tetrahydrofuran (20 ml).
Alla soluzione cosi ottenuta è stato aggiunto lentamente, sotto agitazione a temperatura ambiente, borano-dimetilsolfuro (3,2 g; 40,B mmoli).Al termine dell'aggiunta la miscela di reazione è stata scaldata a riflusso per 1,5 ore. Borane-dimethylsulfide (3.2 g; 40, B mmoles) was slowly added to the solution thus obtained, under stirring at room temperature. At the end of the addition, the reaction mixture was heated under reflux for 1.5 hours.
Dopo raffreddamento a 5°C, è stata aggiunta una soluzione di HCl 37% (1,3 mi) in metanolo (11 ml). After cooling to 5 ° C, a solution of 37% HCl (1.3 ml) in methanol (11 ml) was added.
La miscela di reazione è stata nuovamente scaldata a riflusso per 1 ora, quindi concentrata distillando i solventi a pressione atmosferica e portata a secchezza a pressione ridotta. The reaction mixture was again heated under reflux for 1 hour, then concentrated by distilling the solvents at atmospheric pressure and brought to dryness at reduced pressure.
Il residuo è stato sciolto in metanolo (20 ml) ed il solvente distillato a pressione ridotta. The residue was dissolved in methanol (20 ml) and the solvent distilled under reduced pressure.
Dopo ulteriore aggiunta di metanolo (20 mi) ed evaporazione del solvente a secchezza, il grezzo risultante è stato purificato per cromatografia (eluente After further addition of methanol (20 ml) and evaporation of the solvent to dryness, the resulting crude was purified by chromatography (eluent
Il prodotto ottenuto è stato sciolto in etanolo assoluto (20 mi). Dopo aggiunta di una soluzione di HCl in etere etilico (15% p/v) fino a pH nettamente acido ed evaporazione dei sol venti a pressione ridotta. Composto A (2,1 g) è stato ottenuto come solido bianco amorfo. The product obtained was dissolved in absolute ethanol (20 ml). After addition of a solution of HCl in ethyl ether (15% w / v) up to a clearly acidic pH and evaporation of the solvents at reduced pressure. Compound A (2.1 g) was obtained as an amorphous white solid.
Operando in maniera analoga sono stati preparati i seguenti composti. Operating in a similar manner, the following compounds were prepared.
Esempio 12 Example 12
Preparazione- di (S)-N-propil-N-[6-[2-(4-fenilmetossifenossi)-etilamminolesill-5.6-diidrossi-1.2.3.4-tetraidro-2-naftilammina dicloridrato (Composto D) Preparation- of (S) -N-propyl-N- [6- [2- (4-phenylmethoxyphenoxy) -ethylaminolesyl-5.6-dihydroxy-1.2.3.4-tetrahydro-2-naphthylamine dihydrochloride (Compound D)
Ad una sospensione di Intermedio 2 (6,4 g; 17,2 mmoli), preparato come descritto nell'esempio 1, in cloruro di metilene (52 mi) è stato aggiunto cloruro di tionile (3 g; 25,2 mmoli), sotto azoto a temperatura ambiente. Thionyl chloride (3 g; 25.2 mmol) was added to a suspension of Intermediate 2 (6.4 g; 17.2 mmol), prepared as described in Example 1, in methylene chloride (52 ml), under nitrogen at room temperature.
Dopo 1 ora il solvente è stato evaporato a pressione ridotta ottenendo un olio che è stato sciolto in cloruro di metilene (17 ml) After 1 hour the solvent was evaporated under reduced pressure obtaining an oil which was dissolved in methylene chloride (17 ml)
Ad una soluzione di (S)-N-propil-5,6-diidrossi-1,2,3,4-tetraidro-2-naftilammina bromidrato (4 g; 13,2 mmoli) in acqua (80 mi) è stato aggiunto sotto azoto tetraborato di sodio (5,3 g; 26,3 mmoli). To a solution of (S) -N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine hydrobromide (4 g; 13.2 mmol) in water (80 ml) was added under sodium nitrogen tetraborate (5.3 g; 26.3 mmol).
Dopo riscaldamento a 70°C fino a completa dissoluzione e raffreddamento a temperatura ambiente, sono stati aggiunti cloruro! di metilene (10 mi), carbonato di potassio (14,2 g; 102,7 mmoli) e,sotto vigorose agitazione, la soluzione in cloruro di metilene sopra preparata. After heating to 70 ° C until complete dissolution and cooling to room temperature, chloride was added! of methylene (10 ml), potassium carbonate (14.2 g; 102.7 mmoles) and, under vigorous stirring, the solution in methylene chloride prepared above.
Dopo 1 ora a temperatura ambiente, la miscela di reazione è stata acidificata con HC137% fino a pH 1 e le fasi sono state separate. After 1 hour at room temperature, the reaction mixture was acidified with HC137% to pH 1 and the phases were separated.
La fase acquosa è stata estratta con cloruro di metilene (50, mi). Le fasi organiche riunite sono state lavate con salamoia leggermente acida per acido cloridrico,anidrificate su solfato! di sodio anidro e portate a secchezza a pressione ridotta. The aqueous phase was extracted with methylene chloride (50, ml). The combined organic phases were washed with slightly acid brine for hydrochloric acid, dried over sulphate! of anhydrous sodium and brought to dryness at reduced pressure.
Il residuo così ottenuto è stato sciolto, sotto azoto a temperatura ambiente, in tetraidrofurano (40 mi). The residue thus obtained was dissolved, under nitrogen at room temperature, in tetrahydrofuran (40 ml).
Alla soluzione così ottenuta è stato aggiunto lentamente, sotto agitazione a temperatura ambiente, borano-dimetilsolfuro (6,2 g; 78,9 mmoli).Al termine dell aggiunta la miscela di reazione è stata scaldata a riflusso per 1,5 ore. Borane-dimethyl sulfide (6.2 g; 78.9 mmol) was slowly added to the solution thus obtained, under stirring at room temperature. At the end of the addition, the reaction mixture was heated under reflux for 1.5 hours.
Dopo raffreddamento a 5°C, è stata aggiunta una soluzione di HC1 37% (3 ml) in metanolo (27 mi). After cooling to 5 ° C, a solution of 37% HCl (3 ml) in methanol (27 ml) was added.
La miscela di reazione è stata nuovamente scaldata a riflusso per 1 ora, quindi concentrata distillando i solventi a pressione atmosferica e portata a secchezza a pressione ridotta. The reaction mixture was again heated under reflux for 1 hour, then concentrated by distilling the solvents at atmospheric pressure and brought to dryness at reduced pressure.
Il residuo è stato sciolto in metanolo (50 mi) ed il solvente distillato a pressione ridotta. The residue was dissolved in methanol (50 ml) and the solvent distilled under reduced pressure.
Dopo ulteriore aggiunta di metanolo (50 mi) ed evaporazione del solvente fino a secchezza, il residuo risultante è stato sciolto in etanolo assoluto (50 mi).Dopo aggiunta di una soluzione di HCl in etere etilico (15% p/v) (2 mi) ed evaporazione dei' solventi a pressione ridotta, il grezzo è stato purificato per cromatografia (eluente After further addition of methanol (50 ml) and evaporation of the solvent to dryness, the resulting residue was dissolved in absolute ethanol (50 ml). After addition of a solution of HCl in ethyl ether (15% w / v) (2 ml) and evaporation of the solvents under reduced pressure, the crude was purified by chromatography (eluent
Il solido così ottenuto è stato sciolto in etanolo assoluto (50 mi); dopo aggiunta di una soluzione di HC1 in etere etilico (15% p/v) fino a pH nettamente acido ed evaporazione dei solventi a pressione ridotta, Composto D (4 g) è stato ottenuto come solido bianco amorfo. The solid thus obtained was dissolved in absolute ethanol (50 ml); after addition of a solution of HCl in ethyl ether (15% w / v) up to a clearly acid pH and evaporation of the solvents under reduced pressure, Compound D (4 g) was obtained as an amorphous white solid.
Operando in maniera analoga sono stati preparati i seguenti composti. Operating in a similar manner, the following compounds were prepared.
-5.6-diidrossi-1 .2.3.4-tetraidro-2-naftilammina cloridrato (Composto E) a partire da Intermedio 12. -5.6-dihydroxy-1 .2.3.4-tetrahydro-2-naphthylamine hydrochloride (Compound E) starting from Intermediate 12.
Nassa: 638 [M+1]. Keepnet: 638 [M + 1].
(S)-N-propil-N-[6-[3-(2-metossifenil)proPilammino]esil]-5.6--diidrossi-1.2.3.4-tetraidro-2-naftilammina dicloridrato (Composto F) a partire da Intermedio 6. (S) -N-propyl-N- [6- [3- (2-methoxyphenyl) proPylamino] hexyl] -5.6 - dihydroxy-1.2.3.4-tetrahydro-2-naphthylamine dihydrochloride (Compound F) starting from Intermediate 6 .
Esempio 13 Example 13
Preparazione di (S)-N-propil-N-[6-[2-(3-cloro-4-idrossifenil)-! etilammino]esil]-5.6-dimetossi-1.2.3.4-tetraidro-2-naftilammina dicloridrato (Composto G) Preparation of (S) -N-propyl-N- [6- [2- (3-chloro-4-hydroxyphenyl) -! ethylamino] hexyl] -5.6-dimethoxy-1.2.3.4-tetrahydro-2-naphthylamine dihydrochloride (Compound G)
Ad una soluzione di Intermedio 14 (2,2 g; 5,3 mmoli),preparato come descritto nell’esemiio 5, in cloruro di metilene (4 mi) sono stati aggiunti, sotto azoto a 0°C, N.N-dimetilformamraide (2 gocce) e cloruro d'ossalile (0,B g; 6,3.mmoli). N.N-dimethylformamide (2 drops) and oxalyl chloride (0, B g; 6.3 mmoles).
La miscela di reazione è stata mantenuta sotto agitazione a 0°C per 1,5 ore, quindi lasciata riscaldare spontaneamente a temperatura ambiente. The reaction mixture was kept under stirring at 0 ° C for 1.5 hours, then allowed to spontaneously warm up to room temperature.
Dopo evaporazione del solvente a pressione ridotta, il residuo ottenuto è stato sciolto in cloruro di metilene (5 mi). After evaporation of the solvent under reduced pressure, the residue obtained was dissolved in methylene chloride (5 ml).
La soluzione è stata aggiunta goccia a goccia, sotto azoto a temperatura ambiente,ad una soluzione di Intermedio 17 (1,9 g; 5,3 mmoli),preparato come descritto nell’esempio 6, e trietilammina (1,6 g; 16 mmoli) in cloruro di metilene (5 mi). The solution was added drop by drop, under nitrogen at room temperature, to a solution of Intermediate 17 (1.9 g; 5.3 mmoles), prepared as described in Example 6, and triethylamine (1.6 g; 16 mmoles) in methylene chloride (5 ml).
Dopo 3 ore è stata aggiunta acqua (10 mi), le fasi sono state separate e la fase acquosa è stata estratta con cloruro di metilene (10 mi). After 3 hours, water (10 ml) was added, the phases were separated and the aqueous phase was extracted with methylene chloride (10 ml).
Le fasi organiche riunite sono state anidrificate su solfato di sodio anidro ed il solvente evaporato a pressione ridotta. The combined organic phases were dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure.
Il residuo è stato sciolto in etere etilico (20 mi) ed alla soluzione è stato aggiunto fluoruro di tetrabutilammonio triidrato (3,4 g; 10,8 mmoli). The residue was dissolved in ethyl ether (20 ml) and tetrabutylammonium fluoride trihydrate (3.4 g; 10.8 mmoles) was added to the solution.
Dopo 2 ore sotto agitazione a temperatura ambiente, il solvente è stato evaporato a pressione ridotta ed il residuo è stato ripartito tra acqua e cloruro di metilene. After 2 hours under stirring at room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between water and methylene chloride.
La fase organica è stata anidrificata su solfato di sodio anidro ed il solvente evaporato a pressione ridotta. The organic phase was dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure.
Il grezzo risultante è stato purificato per cromatografia (elu- The resulting crude was purified by chromatography (elu-
Operando in maniera analoga è stato preparato il seguente composto. By operating in a similar manner the following compound was prepared.
Ad una soluzione di (S)-N-propil-N-[6-[(3-cloro-4-idrossifenil)acetilanimino]-1-chetoesil]-5,6-dimetossi-1,2,3,4-tetraidro-2-naftilammina (1,7 g; 3,2 mmoli) in tetraidrofurano 10 mi) è stato aggiunto lentamente, sotto agitazione e sotto azoto,borano-dimetilsolfuro (1,6 g; 20,3 mmoli).Al termine dell'aggiunta la miscela di reazione è stata scaldata a riflusso per 1,5 ore. To a solution of (S) -N-propyl-N- [6 - [(3-chloro-4-hydroxyphenyl) acetylanimino] -1-ketohexyl] -5,6-dimethoxy-1,2,3,4-tetrahydro -2-naphthylamine (1.7 g; 3.2 mmol) in 10 ml tetrahydrofuran) borane-dimethyl sulfide (1.6 g; 20.3 mmol) was added slowly, under stirring and under nitrogen. added the reaction mixture was heated under reflux for 1.5 hours.
Dopo raffreddamento a 5°C, è stata aggiunta una soluzione d: HCl 37% (0,8 mi) in metanolo (7 mi). After cooling to 5 ° C, a solution of d: HCl 37% (0.8 ml) in methanol (7 ml) was added.
La miscela di reazione è stata nuovamente scaldata a riflusso per 1 ora, quindi concentrata distillando i solventi a pressione atmosferica e portata a secchezza a pressione ridotta. The reaction mixture was again heated under reflux for 1 hour, then concentrated by distilling the solvents at atmospheric pressure and brought to dryness at reduced pressure.
Il residuo è stato sciolto in metanolo (15 ml) ed il solvente distillato a pressione ridotta. The residue was dissolved in methanol (15 ml) and the solvent distilled under reduced pressure.
Dopo ulteriore aggiunta di metanolo (15 ml) ed evaporazione del solvente fino a secchezza, il residuo risultante è stato sciolto in etanolo assoluto (15 ml). Dopo aggiunta di una soluzione di HCl in etere etilico (15% p/v) (0,5 mi) ed evaporazione dei solventi a pressione ridotta, il grezzo è stato purificato per, cromatografia ( After further addition of methanol (15 ml) and evaporation of the solvent to dryness, the resulting residue was dissolved in absolute ethanol (15 ml). After addition of a solution of HCl in ethyl ether (15% w / v) (0.5 ml) and evaporation of the solvents under reduced pressure, the crude was purified by chromatography (
Il solido così ottenuto è stato sciolto in etanolo assoluto (20, mi); dopo aggiunta di una soluzione di HCl in etere etilico (15% p/v) fino a pH nettamente acido ed evaporazione dei solventi a pressione ridotta, Composto G (1,4 g) è stato ottenuto come solido bianco amorfo. The solid thus obtained was dissolved in absolute ethanol (20, ml); after addition of a solution of HCl in ethyl ether (15% w / v) up to a clearly acid pH and evaporation of the solvents under reduced pressure, Compound G (1.4 g) was obtained as an amorphous white solid.
Operando in maniere analoga è stato preparato il seguente com7 posto.. Operating in a similar way, the following com7 was prepared.
Massa: 514 [M+1]. Mass: 514 [M + 1].
Esempio 14 Example 14
Preparazione di (S)-N-propil-N-[6-[2- (3-metossi-4-idrossifel nil)etilamminolesill-5.6-di(fenilmetossi)-1 .2.3.4-tetraidro-2-naftilammina dicloridrato (Composto J) Preparation of (S) -N-propyl-N- [6- [2- (3-methoxy-4-hydroxyphelyl) ethylaminolesyl-5.6-di (phenylmethoxy) -1 .2.3.4-tetrahydro-2-naphthylamine dihydrochloride ( Compound J)
Ad una soluzione di intermedio 16 (1,8 g; 4,4 mmoli),preparato come descritto nell'esempio 5, in cloruro di metilene (3 ml) sono stati aggiunti, sotto azoto a 0°C, N,N-diroetilformammidé (2 gocce) e cloruro d'ossalile (0,7 g; 5,5 mmoli). To a solution of intermediate 16 (1.8 g; 4.4 mmoles), prepared as described in Example 5, in methylene chloride (3 ml), N, N-diroethylformamide were added under nitrogen at 0 ° C (2 drops) and oxalyl chloride (0.7 g; 5.5 mmol).
La miscela di reazione è stata mantenuta sotto agitazione a 0°C per 1,5 ore,quindi lasciata riscaldare spontaneamente a tempe-, ratura ambiente. The reaction mixture was kept under stirring at 0 ° C for 1.5 hours, then allowed to spontaneously warm up to room temperature.
Dopo evaporazione del solvente a pressione ridotta, il residuo ottenuto è stato sciolto in cloruro di metilene (3 mi). After evaporation of the solvent under reduced pressure, the residue obtained was dissolved in methylene chloride (3 ml).
La soluzione è stata aggiunta goccia a goccia, sotto azoto a temperatura ambiente, ad una soluzione di Intermedio 20 (2,3 g; 4,4 mmoli),preparato come descritto nell'esempio 9, e trietilammina (1,3 g; 13,1 mmoli) in cloruro di metilene (3 mi). The solution was added drop by drop, under nitrogen at room temperature, to a solution of Intermediate 20 (2.3 g; 4.4 mmoles), prepared as described in example 9, and triethylamine (1.3 g; 13 , 1 mmol) in methylene chloride (3 ml).
Dopo 4 ore è stata aggiunta acqua (10 mi), le fasi sono state separate e la fase acquosa è stata estratta con cloruro di metilene (10 mi). After 4 hours, water (10ml) was added, the phases were separated and the aqueous phase was extracted with methylene chloride (10ml).
Le fasi organiche riunite sono state anidrificate su solfato di sodio anidro ed il solvente evaporato a pressione ridotta. The combined organic phases were dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure.
Il residuo è stato sciolto in etere etilico (15 mi) ed alla soluzione è stato aggiunto fluoruro di tetrabutilammonio riidrato (2,8 g; 8,9 mmoli) The residue was dissolved in ethyl ether (15 ml) and rehydrated tetrabutylammonium fluoride (2.8 g; 8.9 mmol) was added to the solution.
Dopo 2 ore sotto agitazione a temperatura ambiente, il solvente è stato evaporato a pressione ridotta ed il residuo è stato ripartito tra acqua e cloruro di metilene. After 2 hours under stirring at room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between water and methylene chloride.
La fase organica è stata anidrificata su solfato di sodio ani dro ed il solvente evaporato a pressione ridotta. The organic phase was dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure.
Aduna soluzione di -fenil)acetilamminol-1-chetoesil]-5,6-di(fenilmetossi)-1,2,3,4-tetraidro-2-naftilammina (2,8 g; 4,1 mmoli) in tetraidrofurano (25 ml) è stato aggiunto lentamente, sotto agitazione e sotti azoto,borano-dimetilsolfuro (1,9 g; 24,2 mmoli). Al termine dell'aggiunta la miscela di reazione è stata scaldata a riflusso per 1,5 ore. Aduna solution of -phenyl) acetylaminol-1-ketohexyl] -5,6-di (phenylmethoxy) -1,2,3,4-tetrahydro-2-naphthylamine (2.8 g; 4.1 mmol) in tetrahydrofuran (25 ml) borane-dimethyl sulfide (1.9 g; 24.2 mmoles) was slowly added under stirring and under nitrogen. At the end of the addition the reaction mixture was heated under reflux for 1.5 hours.
Dopo raffreddamento a 5°C, è stata aggiunta una soluzione di HC1 37% (0,9 ml) in metanolo (8 mi). After cooling to 5 ° C, a solution of 37% HCl (0.9 ml) in methanol (8 ml) was added.
La miscela di reazione è stata nuovamente scaldata a per 1 ora, quindi concentrata distillando i solventi a pressione atmosferica e portata a secchezza a pressione ridotta. The reaction mixture was heated again at for 1 hour, then concentrated by distilling the solvents at atmospheric pressure and brought to dryness at reduced pressure.
Il residuo è stato sciolto in metanolo (20 mi) ed il solvente distillato a pressione ridotta. The residue was dissolved in methanol (20 ml) and the solvent distilled under reduced pressure.
Dopo ulteriore aggiunta di metanolo (20 ml) ed evaporazione de], solvente fino a secchezza, il residuo risultante è stato sciolto in etanolo assoluto (20 ml). Dopo aggiunta di una soluzione di HC1 in etere etilico (15% p/v) (0,5 ml) ed evaporazione dei solventi a pressione ridotta, il grezzo è stato purificato per cromatografia After further addition of methanol (20 ml) and evaporation of the solvent to dryness, the resulting residue was dissolved in absolute ethanol (20 ml). After addition of a solution of HCl in ethyl ether (15% w / v) (0.5 ml) and evaporation of the solvents under reduced pressure, the crude was purified by chromatography
Il solido così ottenuto è stato sciolto in etanolo assoluto (20 ml);dopo aggiunta di una soluzione di HCl in etere etilico (15% p/v) fino a pH nettamente acido ed evaporazione dei solventi a pressione ridotta, Composto J (1,5 g) è stato ottenuto come solido bianco amorfo. The solid thus obtained was dissolved in absolute ethanol (20 ml); after addition of a solution of HCl in ethyl ether (15% w / v) up to a clearly acid pH and evaporation of the solvents under reduced pressure, Compound J (1, 5 g) was obtained as an amorphous white solid.
Ad una soluzione di acido 3-(3,4-dimetossifenil)propionicq (1,4 g; 6,6 amoli) in cloruro di metilene (10 ml) sono stati aggiunti N.N-dimetilformanmide (2 gocce) e cloruro di tionile (1,2 g; 10,1 mmoli), sotto azoto a temperatura ambiente. N-dimethylformanmide (2 drops) and thionyl chloride (1 , 2 g; 10.1 mmol), under nitrogen at room temperature.
Dopo 1 ora il solvente è stato evaporato a pressione ridotta ottenendo un olio che è stato sciolto in cloruro di metilene (5 ml). After 1 hour the solvent was evaporated under reduced pressure obtaining an oil which was dissolved in methylene chloride (5 ml).
Ad una soluzione di Intermedio 17 (2 g; 5,5 mmoli), preparato come descritto nell’esempio 6, in cloruro di metilene (15 ml), mantenuta sotto agitazione a temperatura ambiente, sono state aggiunte trietilammina (0,8 g; 7,9 mmoli) e la soluzione in cloruro di metilene sopra preparata. Triethylamine (0.8 g; 7.9 mmoles) and the solution in methylene chloride prepared above.
La miscela di reazione è stata mantenuta sotto agitazione a temperatura ambiente per 3 ore. The reaction mixture was kept under stirring at room temperature for 3 hours.
Dopo aggiunta di acqua (30 ml) e separazione delle fasi, la fase organica è stata anidrificata su solfato di sodio ed il solvente evaporato a pressione ridotta. After addition of water (30 ml) and separation of the phases, the organic phase was dried over sodium sulphate and the solvent evaporated under reduced pressure.
Il residuo cosi ottenuto è stato sciolto in tetraidrofurano (15 ml). The residue thus obtained was dissolved in tetrahydrofuran (15 ml).
Alla soluzione così ottenuta è stato aggiunto lentamente, sotto agitazione e sotto azoto a temperatura ambiente, borano-dimetilsolfuro (2,6 g; 32,5 mmoli).Al termine dell'aggiunta la miscela di reazione è stata scaldata a riflusso per 1,5 ore. Dopo raffreddamento a 5°C, è stata aggiunta una soluzione di HC1 37% (1 ml) in metanolo (7,5 ml). Borane-dimethyl sulfide (2.6 g; 32.5 mmoles) was slowly added to the solution thus obtained, under stirring and under nitrogen at room temperature. At the end of the addition, the reaction mixture was heated under reflux for 1. 5 hours. After cooling to 5 ° C, a solution of 37% HCl (1 ml) in methanol (7.5 ml) was added.
a miscela di reazione è stata nuovamente scaldata a per 1 ora,quindi concentrata distillando i solventi a pressione atmosferica e portata a secchezza a pressione ridotta. The reaction mixture was heated again at for 1 hour, then concentrated by distilling the solvents at atmospheric pressure and brought to dryness at reduced pressure.
Il residuo è stato sciolto in metanolo (30 ml) ed il solvente distillato a pressione ridotta. The residue was dissolved in methanol (30 ml) and the solvent distilled under reduced pressure.
Dopo ulteriore aggiunta di metanolo (30 ml) ed evaporazione dei. solvente fino a secchezza, il residuo risultante è stato sciolto in etanolo assoluto (30 ml).Dopo aggiunta di una soluzione di HC1 in etere etilico (15% p/v) (1 mi) ed evaporazione dei! solventi a pressione ridotta, il grezzo è stato purificato per cromatografia (eluente After further addition of methanol (30 ml) and evaporation of the. solvent to dryness, the resulting residue was dissolved in absolute ethanol (30 ml). After addition of a solution of HCl in ethyl ether (15% w / v) (1 ml) and evaporation of the! solvents at reduced pressure, the crude was purified by chromatography (eluent
Il solido cosi ottenuto è stato sciolto in etanolo assoluto; dopo aggiunta di una soluzione di HCl in etere etilico (15% p/v) fino a pH nettamente acido ed evaporazione dei solventi a pressione ridotta, Composto K (1,3 g) è stato ottenuto come solido bianco amorfo. The solid thus obtained was dissolved in absolute ethanol; after addition of a solution of HCl in ethyl ether (15% w / v) up to a clearly acid pH and evaporation of the solvents under reduced pressure, Compound K (1.3 g) was obtained as an amorphous white solid.
Operando in maniera analoga è stato preparato il seguente composto. By operating in a similar manner the following compound was prepared.
(S)-N-propil-N-[6-2-(3-metil-4-metossifenil)etilamminolesill-5.6-dimetossi-1.2.3.4-tetraidro -naftilammina dicloridrato (Composto L) a partire da acido (3-metil-4-metossifenil)acetico. (S) -N-propyl-N- [6-2- (3-methyl-4-methoxyphenyl) ethylaminolesyl-5.6-dimethoxy-1.2.3.4-tetrahydro-naphthylamine dihydrochloride (Compound L) starting from acid (3-methyl -4-methoxyphenyl) acetic.
Esempio 16 Example 16
Preparazione di (S)-N-propil-N-[6-(4-(4-metossifenilmetil) piperazin-1-illesil]-5.6-dimetossi-1.2.3.4-tetraidro-2-naftilammina tricloridrato (Composto M) Preparation of (S) -N-propyl-N- [6- (4- (4-methoxyphenylmethyl) piperazin-1-illesyl] -5.6-dimethoxy-1.2.3.4-tetrahydro-2-naphthylamine trichlorhydrate (Compound M)
Ad una soluzione di Intermedio 21 (2,3 g; 6,1 trottoli), preparato come descritto nell'esempio 10, in cloruro di metilene (15 ml) è stato aggiunto cloruro di tionile (1,1 g; 9,2 mmoli), sotto azoto a temperatura ambiente. To a solution of Intermediate 21 (2.3 g; 6.1 spins), prepared as described in example 10, in methylene chloride (15 ml) was added thionyl chloride (1.1 g; 9.2 mmol ), under nitrogen at room temperature.
Dopo 1 ora il solvente è stato evaporato a pressione ridotta ottenendo un olio che è stato sciolto in cloruro di metilene (5 ml). After 1 hour the solvent was evaporated under reduced pressure obtaining an oil which was dissolved in methylene chloride (5 ml).
Ad una soluzione di Intermedio 13 (1,2 g; 5,8 mmoli),preparato come descritto nell'esempio 4, e trietilammina (0,8 g; 7,9 mmoli) in cloruro di metilene (15 ml), mantenuta sotto agitazione a temperatura ambiente, è stata aggiunta la soluzione in cloruro di metilene sopra preparata. To a solution of Intermediate 13 (1.2 g; 5.8 mmol), prepared as described in Example 4, and triethylamine (0.8 g; 7.9 mmol) in methylene chloride (15 ml), kept under stirring at room temperature, the solution in methylene chloride prepared above was added.
La miscela di reazione è stata mantenuta sotto agitazione a temperatura ambiente per 2 ore. The reaction mixture was kept under stirring at room temperature for 2 hours.
Dopo aggiunta di acqua (30 ml) e separazione delle fasi, la fase acquosa è stata estratta con cloruro di metilene (20 mi). Le fasi organiche riunite sono state lavate con acqua, anidrificate su solfato di sodio ed il solvente evaporato a pressione ridotta. After addition of water (30 ml) and separation of the phases, the aqueous phase was extracted with methylene chloride (20 ml). The combined organic phases were washed with water, dried over sodium sulphate and the solvent evaporated under reduced pressure.
Il residuo così ottenuto è stato sciolto in tetraidrofurano (15 ml). The residue thus obtained was dissolved in tetrahydrofuran (15 ml).
Alla soluzione così ottenuta è stato aggiunto lentamente, sotti agitazione e sotto azoto a temperatura ambiente, borano-dimetilsolfuro (3,3 g; 42 mmoli). Al termine dell'aggiunta la miscela di reazione è stata scaldata a riflusso per 1,5 ore. To the solution thus obtained, borane-dimethylsulfide (3.3 g; 42 mmoles) was slowly added under stirring and under nitrogen at room temperature. At the end of the addition the reaction mixture was heated under reflux for 1.5 hours.
Dopo raffreddamento a 5°C, è stata aggiunta una soluzione di HC1 37% (1,4 ml) in metanolo (12 ml). After cooling to 5 ° C, a solution of 37% HCl (1.4 ml) in methanol (12 ml) was added.
La miscela di reazione è stata nuovamente scaldata a riflusso per 1 ora, quindi concentrata distillando i solventi a pressione atmosferica e portata a secchezza a pressione ridotta. The reaction mixture was again heated under reflux for 1 hour, then concentrated by distilling the solvents at atmospheric pressure and brought to dryness at reduced pressure.
Il residuo è stato sciolto in metanolo (30 mi) ed il solvente distillato a pressione ridotta. The residue was dissolved in methanol (30 ml) and the solvent distilled under reduced pressure.
Dopo ulteriore aggiunta di metanolo (30 mi) ed evaporazione del solvente fine a secchezza, il residuo risultante è stato sciolto in etanolo assoluto (30 mi). Dopo aggiunta di una soluzione di HC1 in etere etilico (15% p/v) (1 ml), i solventi sono stati evaporati ottenendo Composto M (2,5 g) come solido bianco amorfo. After further addition of methanol (30 ml) and evaporation of the fine solvent to dryness, the resulting residue was dissolved in absolute ethanol (30 ml). After addition of a solution of HCl in ethyl ether (15% w / v) (1 ml), the solvents were evaporated to obtain Compound M (2.5 g) as an amorphous white solid.
Esempio 17 Example 17
Preparazione di_ (S)-N-ProPÌl-N-[6-[(3-4-dimetossifenil)acetilamminolesil)1-5.6-dimetossi-1.2.3.4-tetraidro-2-naftilammina (Composto N) Preparation of_ (S) -N-ProPIl-N- [6 - [(3-4-dimethoxyphenyl) acetylaminolesyl) 1-5.6-dimethoxy-1.2.3.4-tetrahydro-2-naphthylamine (Compound N)
Ad una soluzione di acido (3,4-dimetossifenil)acetico (0,8 g;j 4,1 mmoli) in cloruro di metilene (7 ml) sono stati aggiunti N,N-dimetilformammide (2 gocce) e cloruro di tionile (0,8 g; 6,7 mmoli), sotto azoto a temperatura ambiente. N, N-dimethylformamide (2 drops) and thionyl chloride ( 0.8 g; 6.7 mmol), under nitrogen at room temperature.
Dopo 1 ora il solvente è stato evaporato a pressione ridotta ottenendo un olio che è stato sciolto in cloruro di metilene (5 ml). After 1 hour the solvent was evaporated under reduced pressure obtaining an oil which was dissolved in methylene chloride (5 ml).
Ad una soluzione di Intermedio 18 (1,4 g; 3,3 mmoli),preparato come descritto nell'esempio 7, e trietilammina (1,2 g; 11,9 mmoli) in cloruro di metilene (14 ml),mantenuta sotto agitazione a temperatura ambiente, è stata aggiunta la soluzione ini cloruro di metilene sopra preparata. To a solution of Intermediate 18 (1.4 g; 3.3 mmol), prepared as described in example 7, and triethylamine (1.2 g; 11.9 mmol) in methylene chloride (14 ml), kept under stirring at room temperature, the above prepared methylene chloride solution was added.
La miscela di reazione è stata mantenuta sotto agitazione a temperatura ambiente per 3 ore e quindi versata in acqua (25 ml). The reaction mixture was kept under stirring at room temperature for 3 hours and then poured into water (25 ml).
Dopo separazione dèlie fasi, la fase acquosa è stata estratta con cloruro di metilene (25 ml) e le fasi organiche riunite sono state lavate con acqua, anidrificate su solfato di sodio ed il solvente evaporato a pressione ridotta. After separation of the phases, the aqueous phase was extracted with methylene chloride (25 ml) and the combined organic phases were washed with water, dried over sodium sulphate and the solvent evaporated under reduced pressure.
Il grezzo risultante è stato purificato per cromatografia (elu ente :ammoniaca 303⁄4=95:5:0,5) ottenendo Composto N The resulting crude was purified by chromatography (elu ent: ammonia 303⁄4 = 95: 5: 0.5) obtaining Compound N
Esempio 1B Example 1B
Preparazione di (S)-N-propil-N-[6-[(1.4-benzodiossan-2 metilammino]esil]-5.6-diidrossi-1,2.3.4-tetraidro-2-naftilammina dicloridrato (Composto 1) Preparation of (S) -N-propyl-N- [6 - [(1.4-benzodioxan-2 methylamino] hexyl] -5.6-dihydroxy-1,2.3.4-tetrahydro-2-naphthylamine dihydrochloride (Compound 1)
Operando in maniera analoga a quanto descritto nell'esempio 12 ma utilizzando Intermedio 5 invece di Intermedio 2, è stato ottenuto Composto 1. By operating in the same way as described in example 12 but using Intermediate 5 instead of Intermediate 2, Compound 1 was obtained.
Analogamente sono stati ottenuti i seguenti composti. Similarly, the following compounds were obtained.
(S)-N-propil-N-[6-[2-(3.4-ma_tilendiossifenil)etilammino ]esil]-5.6-diidrossi-1.2.3.4-tetraidro-2-naftilammina dicloridrato (Composto 2) a partire da Intermedio 4. (S) -N-propyl-N- [6- [2- (3.4-ma_tylenedioxyphenyl) ethylamino] hexyl] -5.6-dihydroxy-1.2.3.4-tetrahydro-2-naphthylamine dihydrochloride (Compound 2) starting from Intermediate 4.
5.6-diidrossi-1.2.3.4-tetraidro-2-naftilammina- dicloridrato (Composto 6) a partire da Intermedio 9. 5.6-dihydroxy-1.2.3.4-tetrahydro-2-naphthylamine-dihydrochloride (Compound 6) starting from Intermediate 9.
Esempio 19 Example 19
Ad una sospensione di acido (2-metossifenossi)acetico (0,6 g; 3,3 mmoli) in cloruro di metilene (10 ml) sono stati aggiunti N,N-dimetilformammide (2 gocce) e cloruro di tionile (0,6 g; 5 mmoli), sotto azoto a temperatura ambiente. N, N-dimethylformamide (2 drops) and thionyl chloride (0.6 g; 5 mmol), under nitrogen at room temperature.
Dopo 3 ore il solvente è stato evaporato a pressione ridotta ottenendo un olio che è stato sciolto in cloruro di metilene (5 ml). After 3 hours the solvent was evaporated under reduced pressure obtaining an oil which was dissolved in methylene chloride (5 ml).
Ad una soluzione di Intermedio 19 (1,2 g; 2,5 mmoli),preparato come descritto nell’esempio 8, in acqua (15 ml) è stato aggiunto sotto azoto tetraborato di sodio (1 g; 5 mmoli). Sodium tetraborate (1 g; 5 mmol) was added under nitrogen to a solution of Intermediate 19 (1.2 g; 2.5 mmol), prepared as described in Example 8, in water (15 ml).
Dopo riscaldamento a 70°C fino a completa dissoluzione e raffreddamento a temperatura ambiente, sono stati aggiunti cloruro di metilene (2 mi), carbonato di potassio (2,7 g; 19,5 mmoli) e, sotto vigorosa agitazione, la soluzione- in cloruro di metilene sopra preparata. After heating to 70 ° C until complete dissolution and cooling to room temperature, methylene chloride (2 ml), potassium carbonate (2.7 g; 19.5 mmol) and, under vigorous stirring, the solution were added. in methylene chloride prepared above.
Dopo 1 ora a temperatura ambiente, la miscela di reazione è stata acidificata con fino a pH 1 e le fasi sono state separate. After 1 hour at room temperature, the reaction mixture was acidified to pH 1 and the phases were separated.
La fase acquosa è stata estratta con cloruro di metilene (15 ml). Le fasi organiche riunite sono state lavate con salamoia leggermente acida per acido cloridrico, anidrificate su solfato di sodio anidro e portate a secchezza a pressione ridotte. The aqueous phase was extracted with methylene chloride (15 ml). The combined organic phases were washed with slightly acid brine for hydrochloric acid, dried over anhydrous sodium sulphate and dried under reduced pressure.
Il residuo risultante è stato purificato per cromatografia (eluente The resulting residue was purified by chromatography (eluent
Il solido ottenuto è stato sciolto in etanolo assoluto. The solid obtained was dissolved in absolute ethanol.
Dopo aggiunta di una soluzione di acido cloridrico in etere etilico (15% p/v) fino a pH nettamente acido, i solventi sono stati evaporati a pressione ridotta ottenendo Composto 7 (0,9 g) come solido amorfo bianco. After adding a solution of hydrochloric acid in ethyl ether (15% w / v) up to a clearly acidic pH, the solvents were evaporated under reduced pressure to obtain Compound 7 (0.9 g) as a white amorphous solid.
Esempio 20 Example 20
Una soluzione di Composto A (1,9 g; 3,2 mmoli),preparato come descritto nell'esempio 11, in acido bromidrico 48% (19 ml) è stata scaldata a riflusso sotto azoto per 5 ore. A solution of Compound A (1.9 g; 3.2 mmoles), prepared as described in example 11, in 48% hydrobromic acid (19 ml) was refluxed under nitrogen for 5 hours.
La miscela di reazione è stata quindi portata a secchezza a pressione ridotta ed al residuo così ottenuto è stato aggiunto etanolo assoluto (40 ml). The reaction mixture was then brought to dryness under reduced pressure and absolute ethanol (40 ml) was added to the residue thus obtained.
Dopo evaporazione del solvente ed aggiunta di acetato d’etile (40 ml), il solvente è stato nuovamente evaporato. After evaporation of the solvent and addition of ethyl acetate (40 ml), the solvent was evaporated again.
Il residuo risultante è stato purificato per cromatografia ottenendo Composto 8 (0,8 g) come solido amorfo bianco. The resulting residue was purified by chromatography to obtain Compound 8 (0.8 g) as a white amorphous solid.
Operando in maniera analoga sono stati preparati i seguenti composti. Operating in a similar manner, the following compounds were prepared.
(S)-N-propil-N-[6-13-(4-idrossifenil)propilamminolesil1-5.6-diidrossi- 1 .2.3.4-tetraidro-2-naftilammina dibromidrato (Composto 9) a partire da Composto B. (S) -N-propyl-N- [6-13- (4-hydroxyphenyl) propylaminolesyl1-5.6-dihydroxy- 1 .2.3.4-tetrahydro-2-naphthylamine dibromide (Compound 9) starting from Compound B.
(Composto 11) a partire da Composto G. (Compound 11) starting from Compound G.
5.6-diidrossi-1 .2.3. 4-tetraidro-2-naf tilammina -dibromidrato 5.6-dihydroxy-1 .2.3. 4-tetrahydro-2-naphthylamine -dhybromide
Esempio 21 Example 21
Preparazione di (S)-N-propil-N-[6-[2- (4-idrossifenossi)etilammino ]esil]-5.6-diidrossi-1 .2.3 .4-tetraidro-2-naftilammina dicloridrato (Composto 173 Preparation of (S) -N-propyl-N- [6- [2- (4-hydroxyphenoxy) ethylamino] hexyl] -5.6-dihydroxy-1 .2.3 .4-tetrahydro-2-naphthylamine dihydrochloride (Compound 173
Ad una soluzione di Composto D (3,4 g; 5,5 mmoli), preparato come descritto nell'esempio 12, in etanolo assoluto (100 mi) sono stati aggiunti HC1 37% (1 mi) e palladio su carbone 10% (50% acqua) (0,7 g). To a solution of Compound D (3.4 g; 5.5 mmoles), prepared as described in example 12, 37% HCl (1 ml) and palladium on carbon 10% ( 50% water) (0.7 g).
La miscela è stata idrogenata in apparecchio Parr (2,7 atm) per 3 ore. The mixture was hydrogenated in a Parr apparatus (2.7 atm) for 3 hours.
Il catalizzatore è stato filtrato e la soluzione è stata portata a secchezza a pressione ridotta. The catalyst was filtered and the solution was brought to dryness under reduced pressure.
Il residuo è stato purificato per cromatografia (eluente The residue was purified by chromatography (eluent
Il solido risultante è stato sciolto in etanolo assoluto (40 mi). Dopo aggiunta di una soluzione di acido cloridrico in etere etilico (15% p/v) fino a pH nettamente acido ed evaporazione dei solventi a pressione ridotta, è stato ottenuto Composto 17 (2,5 g) come solido amorfo bianco. The resulting solid was dissolved in absolute ethanol (40 ml). After addition of a solution of hydrochloric acid in ethyl ether (15% w / v) up to a clearly acidic pH and evaporation of the solvents under reduced pressure, Compound 17 (2.5 g) was obtained as a white amorphous solid.
Operando in maniera analoga sono stati preparati i seguenti composti. Operating in a similar manner, the following compounds were prepared.
Esempio 22 Example 22
Preparazione di- (S)-N-propil-N-[6-[(3.4-diidrossifenil)acetil-l ammino]esin-5.6zdlldrossi-l.2.3.4-tetraidro-2-naftilammina bromidrato (Composto 20) Preparation of- (S) -N-propyl-N- [6 - [(3.4-dihydroxyphenyl) acetyl-1 amino] hexine-5.6zdlldroxy-1,2.3.4-tetrahydro-2-naphthylamine hydrobromide (Compound 20)
Ad una soluzione di Composto N (0,6 g; 1,1 mmoli), preparato come descritto nell'esempio 17, in cloruro di metilene (8 mi) è stata aggiunta, sotto azoto a 0°C,una soluzione 1M di tribromuro di boro in cloruro di metilene (4,7 mi). A 1M solution of tribromide was added under nitrogen at 0 ° C to a solution of Compound N (0.6 g; 1.1 mmoles), prepared as described in example 17, in methylene chloride (8 ml). of boron in methylene chloride (4.7 ml).
La miscela di reazione è stata lasciata riscaldare spontaneamente fino a temperatura ambiente. The reaction mixture was allowed to spontaneously warm up to room temperature.
Dopo 3 ore a temperatura ambiente è stato aggiunto metanolo (5 ml) e la soluzione risultante è stata portata a secchezza a pressione ridotta. After 3 hours at room temperature methanol (5 ml) was added and the resulting solution was brought to dryness under reduced pressure.
Il grezzo è stato purificato per cromatografia (eluente ottenendo Composto 20 (0,6 g) come solido amorfo bianco. The crude was purified by chromatography (eluent to obtain Compound 20 (0.6 g) as a white amorphous solid.
Esempio 23 Example 23
valutazione dell'affinità verso i recettori D-, e D, Cervelli di ratti maschi Sprague-Dauley (200-250 g) sono stati rimossi e le membrane di tessuti striatali sono state preparate secondo la metodica descritta da Billard et al. in Life Sciences, 1885, (1984). evaluation of the affinity towards the D-, and D receptors, Brains of male Sprague-Dauley rats (200-250 g) were removed and the membranes of striatal tissues were prepared according to the method described by Billard et al. in Life Sciences, 1885, (1984).
I tessuti sono stati omogeneizzati in tampone 50 mM Tris/HCl a pH 7,4 (1:100 p/v). Tissues were homogenized in 50 mM Tris / HCl buffer at pH 7.4 (1: 100 w / v).
L'omogenato è stato centrifugato ed il pellet risospeso, ricentrifugato e risospeso nuovamente in tampone 50 mM Tris/HC1 a pH 7,4 contenente 120 mM NaCl, 5mM KC1, 2 mM CaCl2 e 1 mM MgCl2. L’affinità verso il recettore D1 ed il recettore D2 è stata valutata usando rispettivamente [aH]-SCH23390 [R(+)-8-cloro-2,3,4,5-tetraidro-3-metil-5-fenil-1H-3-benzazepina 7-olo cloridrato] e [3H]-domperidone (The Merck Index - XI ed., n° 3412, pag. 537) come leganti marcati. The homogenate was centrifuged and the pellet resuspended, re-centrifuged and resuspended again in 50 mM Tris / HC1 buffer at pH 7.4 containing 120 mM NaCl, 5mM KC1, 2 mM CaCl2 and 1 mM MgCl2. Affinity towards D1 receptor and D2 receptor was evaluated using [aH] -SCH23390 [R (+) - 8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H, respectively -3-benzazepine 7-ol hydrochloride] and [3H] -domperidone (The Merck Index - XI ed., N ° 3412, p. 537) as labeled ligands.
Come sostanza di riferimento sono state usate dopamina, dopexamina ed (S)-N-propil-N-[6-[2-(2-metossifenil)etilammino]esil]-5,6-diidrossi-1,2,3,4-tetraidro-2-naftilammina dicloidrato (Rif.A),descritta nell’esempio 6 della domanda di brevetto intemazionale WO 93/19036. Dopamine, dopexamine and (S) -N-propyl-N- [6- [2- (2-methoxyphenyl) ethylamino] hexyl] -5,6-dihydroxy-1,2,3,4 were used as reference substance -tetrahydro-2-naphthylamine diclohydrate (Ref.A), described in example 6 of the international patent application WO 93/19036.
Le condizioni di incubazione standard (volume 1000 pi) per il saggio in cui è stato usato [3H]-SCH23390 sono le seguenti: 50 mM tampone Tris/HCl (pH 7,4), 0,2 nM [3H]-SCH23390, una preparazione di membrane di 130-140 pg proteine/ml. The standard incubation conditions (1000 µl volume) for the assay in which [3H] -SCH23390 was used are as follows: 50 mM Tris / HCl buffer (pH 7.4), 0.2 nM [3H] -SCH23390, a preparation of membranes of 130-140 µg proteins / ml.
La miscela è stata incubate con diverse concentrazioni dei' composti saggiati a 37°C per 20 minuti, filtrata sotto vuoto attraverso filtri Whatman GF/C e quindi lavata 4 volte con 5 mi di tampone 50 mM Tris/HCl (pH 7,4) raffreddato in ghiaccio. Per gli studi di affinità per il recettore Da, [3H]-domperidone (0,3 nM) è stato incubato in un volume di 1000 μl contenente tampone e preparazione di membrane come sopra descritto. The mixture was incubated with different concentrations of the tested compounds at 37 ° C for 20 minutes, filtered under vacuum through Whatman GF / C filters and then washed 4 times with 5 ml of 50 mM Tris / HCl buffer (pH 7.4). cooled in ice. For affinity studies for the Da receptor, [3H] -domperidone (0.3 nM) was incubated in a 1000 μl volume containing buffer and membrane preparation as described above.
Inoltre è stata aggiunta albumina di siero bovino (BSA) (0,01%). In addition, Bovine Serum Albumin (BSA) (0.01%) was added.
La miscela è stata incubata a 37°C per 30 minuti per ogni concentrazione dei composti saggiati. The mixture was incubated at 37 ° C for 30 minutes for each concentration of the tested compounds.
I risultati ottenuti, espressi come K1 (nM), per i composti 1-10, 13, 15-18 e 20, Rif.A, dopamina e dopexamina sono riportati nella seguente tabella. The results obtained, expressed as K1 (nM), for compounds 1-10, 13, 15-18 and 20, Ref.A, dopamine and dopexamine are shown in the following table.
Tabella 1 Table 1
Affinità [K1 (nM)] verso i recettori D1 e D2 dei composti 1-10, 13, 15-18 e 20,Rif. A,dopamina e dopexamina determinata attraverso studi di binding su membrane striatali di ratto. Affinity [K1 (nM)] towards the D1 and D2 receptors of compounds 1-10, 13, 15-18 and 20, Ref. A, dopamine and dopexamine determined through binding studies on rat striatal membranes.
affinitàverso entrambi isottotipi recettoriali risultando moltopiùaffinididopamina edopexaroinae con affinitàalmeno comparabileaquelladelRif.A sia suirecettoriD-1 sia su recettoriD2. affinity towards both receptor isoptypes resulting in much more affinity than dopamine and opexaroin and with an affinity at least comparable to that of Ref.A on both D-1 and D2 receptors.
Claims (8)
Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI941868A IT1271007B (en) | 1994-09-13 | 1994-09-13 | DERIVATIVES OF 2-AMINO-1,2,3,4-TETRAIDRONAFTALENE ACTIVE IN THE CARDIOVASCULAR SYSTEM |
US08/465,636 US5674909A (en) | 1994-09-13 | 1995-06-06 | Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene active on the cardiovascular system |
JP8509893A JPH11501006A (en) | 1994-09-13 | 1995-09-11 | 2-amino-1,2,3,4-tetrahydronaphthalene derivative acting on cardiovascular system |
ES95932708T ES2168384T3 (en) | 1994-09-13 | 1995-09-11 | DERIVATIVES OF 2-AMINO-1,2,3,4-TETRAHIDRONAFTALENO ACTIVE FOR THE CARDIOVASCULAR SYSTEM. |
DE69524610T DE69524610T2 (en) | 1994-09-13 | 1995-09-11 | 2-AMINO-1,2,3,4-TETRAHYDRONAPHTALINE DERIVATIVES WITH CARDIOVASCULAR EFFECT |
NZ293258A NZ293258A (en) | 1994-09-13 | 1995-09-11 | 2-amino-1,2,3,4-tetrahydronaphthalene derivatives |
CA002199484A CA2199484A1 (en) | 1994-09-13 | 1995-09-11 | Derivatives of 2-amino-1,2,3,4-tetrahydro-naphthalene active on the cardiovascular system |
CZ97765A CZ76597A3 (en) | 1994-09-13 | 1995-09-11 | 2-amino-1,2,3,4-tetrahydronaphthalene derivatives, process of their preparation and pharmaceutical composition containing thereof |
RU97106097/04A RU2149158C1 (en) | 1994-09-13 | 1995-09-11 | 2-amino-1,2,3,4-tetrahydronaphthalene derivatives having activity with respect to cardiovascular system, and pharmaceutical composition |
DK95932708T DK0781126T3 (en) | 1994-09-13 | 1995-09-11 | Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene active on the cardiovascular system |
AU35653/95A AU694563B2 (en) | 1994-09-13 | 1995-09-11 | Derivatives of 2-amino-1,2,3,4-tetrahydro-naphthalene active on the cardiovascular system |
PCT/EP1995/003562 WO1996008228A2 (en) | 1994-09-13 | 1995-09-11 | Derivatives of 2-amino-1,2,3,4-tetrahydro-naphthalene active on the cardiovascular system |
AT95932708T ATE210433T1 (en) | 1994-09-13 | 1995-09-11 | 2-AMINO-1,2,3,4-TETRAHYDRONAPHTALINE DERIVATIVES WITH CARDIOVASCULAR ACTION |
HU9701331A HUT76837A (en) | 1994-09-13 | 1995-09-11 | Derivatives of 2-amino-1,2,3,4-tetrahydro-naphthalene active on the cardiovascular system, pharmaceutical compositions containing them and process for their preparation |
KR1019970701644A KR970705989A (en) | 1994-09-13 | 1995-09-11 | Amino-1,2,3,4-tetrahydro-naphthalene derivatives which are active against the cardiovascular system (DERIVATIVES OF 2-AMINO-1, 2, 3, 4-TETRAHYDRO- NAPHTHALENE ACTIVE ON THE CARDIOVASCULAR SYSTEM) |
EP95932708A EP0781126B1 (en) | 1994-09-13 | 1995-09-11 | Derivatives of 2-amino-1,2,3,4-tetrahydro-naphthalene active on the cardiovascular system |
PT95932708T PT781126E (en) | 1994-09-13 | 1995-09-11 | 2-AMINO-1,2,3,4-TETRA-HYDRO-NAFTALINO DERIVATIVES ACTIVE IN THE CARDIOVASCULAR SYSTEM |
NO971134A NO971134L (en) | 1994-09-13 | 1997-03-12 | Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene active on the cardiovascular system |
FI971039A FI971039A0 (en) | 1994-09-13 | 1997-03-12 | 2-Amino-1,2,3,4-tetrahydronaphthalene derivatives active in the cardiovascular system |
Applications Claiming Priority (1)
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ITMI941868A IT1271007B (en) | 1994-09-13 | 1994-09-13 | DERIVATIVES OF 2-AMINO-1,2,3,4-TETRAIDRONAFTALENE ACTIVE IN THE CARDIOVASCULAR SYSTEM |
Publications (3)
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ITMI941868A0 ITMI941868A0 (en) | 1994-09-13 |
ITMI941868A1 true ITMI941868A1 (en) | 1996-03-13 |
IT1271007B IT1271007B (en) | 1997-05-26 |
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ITMI941868A IT1271007B (en) | 1994-09-13 | 1994-09-13 | DERIVATIVES OF 2-AMINO-1,2,3,4-TETRAIDRONAFTALENE ACTIVE IN THE CARDIOVASCULAR SYSTEM |
Country Status (19)
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US (1) | US5674909A (en) |
EP (1) | EP0781126B1 (en) |
JP (1) | JPH11501006A (en) |
KR (1) | KR970705989A (en) |
AT (1) | ATE210433T1 (en) |
AU (1) | AU694563B2 (en) |
CA (1) | CA2199484A1 (en) |
CZ (1) | CZ76597A3 (en) |
DE (1) | DE69524610T2 (en) |
DK (1) | DK0781126T3 (en) |
ES (1) | ES2168384T3 (en) |
FI (1) | FI971039A0 (en) |
HU (1) | HUT76837A (en) |
IT (1) | IT1271007B (en) |
NO (1) | NO971134L (en) |
NZ (1) | NZ293258A (en) |
PT (1) | PT781126E (en) |
RU (1) | RU2149158C1 (en) |
WO (1) | WO1996008228A2 (en) |
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IT1271411B (en) * | 1993-09-14 | 1997-05-28 | Zambon Spa | 2-AMINO-1,2,3,4-TETRAIDRO-NAFTALENE DERIVATIVES ACTIVE IN THE CARDIOVASCULAR SYSTEM |
IT1289980B1 (en) * | 1997-02-26 | 1998-10-19 | Zambon Spa | HYDROXYMETHYL DERIVATIVES OF 2-AMINO-1,2,3,4-TETRAIDRONAPHTHALENE ACTIVE IN THE CARDIOVASCULAR FIELD |
DE69921815T2 (en) * | 1998-06-03 | 2005-11-10 | Nissan Chemical Industries, Ltd. | indane derivatives |
DE10109859A1 (en) * | 2001-03-01 | 2002-09-05 | Bayer Ag | Novel aminodicarboxylic acid derivatives |
GB2389582A (en) * | 2002-06-13 | 2003-12-17 | Bayer Ag | Pharmaceutically active carboxamides |
MXPA05011225A (en) * | 2003-04-18 | 2005-12-14 | Pharmacia & Upjohn Co Llc | Combination therapies for chronic obstructive pulmonary disease (copd). |
US8710045B2 (en) | 2004-01-22 | 2014-04-29 | The Trustees Of Columbia University In The City Of New York | Agents for preventing and treating disorders involving modulation of the ryanodine receptors |
KR101589551B1 (en) | 2005-07-15 | 2016-02-02 | 알바니 몰레큘라 리써치, 인크. | Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
JP2010526825A (en) * | 2007-05-10 | 2010-08-05 | エーエムアール テクノロジー インコーポレイテッド | Aryl- and heteroaryl-substituted tetrahydrobenzo-1,4-diazepines and their use to block reuptake of norepinephrine, dopamine and serotonin |
CN103476415B (en) | 2010-11-16 | 2017-09-22 | 南加州大学 | For the CBP/ catenin antagonists for the Asymmetric division for strengthening adult stem cell |
WO2014085600A1 (en) * | 2012-11-29 | 2014-06-05 | Wayne State University | Neuroprotective agents for treatment of neurodegenerative diseases |
US10874669B2 (en) | 2012-11-29 | 2020-12-29 | Wayne State University | Neuroprotective agents for treatment of neurodegenerative diseases |
US11285147B2 (en) | 2018-09-07 | 2022-03-29 | Wayne State University | Neuroprotective agents for treatment of neurodegenerative diseases |
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DK131775A (en) * | 1974-03-28 | 1975-09-29 | Wellcome Found | |
DE3263531D1 (en) * | 1981-08-05 | 1985-06-20 | Fisons Plc | Amine derivatives, processes for their production and pharmaceutical compositions containing them |
DE3484048D1 (en) * | 1983-10-25 | 1991-03-07 | Fisons Plc | PHENYLETHYLAMINE, METHOD FOR THE PRODUCTION THEREOF AND COMPOSITIONS CONTAINING THE SAME. |
US4720586A (en) * | 1983-12-06 | 1988-01-19 | Fisons, Plc | Substituted 3,4-dihydroxy-phenylethylamino compounds |
IT1224405B (en) * | 1987-12-23 | 1990-10-04 | Simes | ACTIVE COMPOUNDS ON THE CARDIOVASCULAR SYSTEM |
US5358971A (en) * | 1989-07-05 | 1994-10-25 | Whitby Research, Inc. | Substituted 2-aminotetralins |
IT1254521B (en) * | 1992-03-17 | 1995-09-25 | Zambon Spa | 2-AMINO-TETRALINE DERIVATIVES ACTIVE IN THE CARDIOVASCULAR SYSTEM |
IT1271411B (en) * | 1993-09-14 | 1997-05-28 | Zambon Spa | 2-AMINO-1,2,3,4-TETRAIDRO-NAFTALENE DERIVATIVES ACTIVE IN THE CARDIOVASCULAR SYSTEM |
-
1994
- 1994-09-13 IT ITMI941868A patent/IT1271007B/en active IP Right Grant
-
1995
- 1995-06-06 US US08/465,636 patent/US5674909A/en not_active Expired - Fee Related
- 1995-09-11 PT PT95932708T patent/PT781126E/en unknown
- 1995-09-11 WO PCT/EP1995/003562 patent/WO1996008228A2/en not_active Application Discontinuation
- 1995-09-11 JP JP8509893A patent/JPH11501006A/en not_active Ceased
- 1995-09-11 NZ NZ293258A patent/NZ293258A/en unknown
- 1995-09-11 CZ CZ97765A patent/CZ76597A3/en unknown
- 1995-09-11 DE DE69524610T patent/DE69524610T2/en not_active Expired - Fee Related
- 1995-09-11 AT AT95932708T patent/ATE210433T1/en not_active IP Right Cessation
- 1995-09-11 EP EP95932708A patent/EP0781126B1/en not_active Expired - Lifetime
- 1995-09-11 HU HU9701331A patent/HUT76837A/en unknown
- 1995-09-11 RU RU97106097/04A patent/RU2149158C1/en not_active IP Right Cessation
- 1995-09-11 DK DK95932708T patent/DK0781126T3/en active
- 1995-09-11 AU AU35653/95A patent/AU694563B2/en not_active Ceased
- 1995-09-11 CA CA002199484A patent/CA2199484A1/en not_active Abandoned
- 1995-09-11 ES ES95932708T patent/ES2168384T3/en not_active Expired - Lifetime
- 1995-09-11 KR KR1019970701644A patent/KR970705989A/en not_active Application Discontinuation
-
1997
- 1997-03-12 FI FI971039A patent/FI971039A0/en unknown
- 1997-03-12 NO NO971134A patent/NO971134L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
NZ293258A (en) | 1998-06-26 |
NO971134D0 (en) | 1997-03-12 |
ES2168384T3 (en) | 2002-06-16 |
CA2199484A1 (en) | 1996-03-21 |
EP0781126B1 (en) | 2001-12-12 |
IT1271007B (en) | 1997-05-26 |
DE69524610D1 (en) | 2002-01-24 |
AU3565395A (en) | 1996-03-29 |
JPH11501006A (en) | 1999-01-26 |
DE69524610T2 (en) | 2002-07-18 |
US5674909A (en) | 1997-10-07 |
WO1996008228A3 (en) | 1996-07-25 |
CZ76597A3 (en) | 1997-10-15 |
RU2149158C1 (en) | 2000-05-20 |
FI971039A (en) | 1997-03-12 |
ITMI941868A0 (en) | 1994-09-13 |
HUT76837A (en) | 1997-11-28 |
EP0781126A2 (en) | 1997-07-02 |
DK0781126T3 (en) | 2002-04-08 |
KR970705989A (en) | 1997-11-03 |
PT781126E (en) | 2002-06-28 |
WO1996008228A2 (en) | 1996-03-21 |
AU694563B2 (en) | 1998-07-23 |
NO971134L (en) | 1997-05-12 |
FI971039A0 (en) | 1997-03-12 |
ATE210433T1 (en) | 2001-12-15 |
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